85 results on '"Tony Avril"'
Search Results
2. A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment
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Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Timothy Langlais, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A. Eriksson, and Xavier Guillory
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Medicine ,Biological sciences ,Neuroscience ,Molecular neuroscience ,Science - Abstract
Summary: Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood–brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB.
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- 2023
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3. Dual IRE1 RNase functions dictate glioblastoma development
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Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares‐Lupon, Kathleen Schmit, Pierre‐Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, and Eric Chevet
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Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Published
- 2023
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4. A cell-based system combined with flow cytometry to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in patients with COVID-19
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Sophie Martin, Gwénaële Jégou, Aurore Nicolas, Matthieu Le Gallo, Éric Chevet, Florence Godey, and Tony Avril
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Cell Biology ,Flow Cytometry/Mass Cytometry ,Cell-based Assays ,Health Sciences ,Microbiology ,Molecular Biology ,Science (General) ,Q1-390 - Abstract
Summary: This protocol describes a flow cytometry approach to evaluate antibody responses against SARS-CoV-2 transmembrane proteins in COVID-19-positive patient sera samples without the need of specific laboratory facilities for viral infection. We developed a human-cell-based system using spike-expressing HEK293T cells that mimics membrane insertion and N-glycosylation of viral integral membrane proteins in host cells. This assay represents a powerful tool to test antibody responses against SARS-CoV-2 variants and vaccine effectiveness.For complete details on the use and execution of this protocol, please refer to Martin et al. (2021).
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- 2022
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5. Dual IRE1 RNase functions dictate glioblastoma development
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Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares‐Lupon, Kathleen Schmit, Pierre‐Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, and Eric Chevet
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Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Published
- 2022
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6. SARS-CoV-2 integral membrane proteins shape the serological responses of patients with COVID-19
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Sophie Martin, Christopher Heslan, Gwénaële Jégou, Leif A. Eriksson, Matthieu Le Gallo, Vincent Thibault, Eric Chevet, Florence Godey, and Tony Avril
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Immunology ,Virology ,Science - Abstract
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat the infection. Like other coronavirae, SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including spike (S), envelope (E), and membrane (M) proteins, the most exposed transmembrane proteins to the host immune system. As antibody response is part of the anti-viral immune arsenal, we investigate the immunogenic potential of S, E, and M using a human cell-based system to mimic membrane insertion and N-glycosylation. Both S and M elicit specific Ig production in patients with SARS-CoV-2. Patients with moderate and severe diseases exhibit elevated Ig responses. Finally, reduced Ig binding was observed with spike G614 compared to D614 variant. Altogether, our assay points toward an unexpected immune response against M and represents a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness.
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- 2021
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7. The expression of EMX2 lead to cell cycle arrest in glioblastoma cell line
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Annabelle Monnier, Rachel Boniface, Régis Bouvet, Amandine Etcheverry, Marc Aubry, Tony Avril, Véronique Quillien, Eric Chevet, and Jean Mosser
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Glioblastoma - reversible phenotype ,Cell proliferation ,Cell cycle arrest ,Transcriptome analysis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Glioblastoma (GB) is a highly invasive primary brain tumor that nearly always systematically recurs at the site of resection despite aggressive radio-chemotherapy. Previously, we reported a gene expression signature related to tumor infiltration. Within this signature, the EMX2 gene encodes a homeodomain transcription factor that we found was down regulated in glioblastoma. As EMX2 is reported to play a role in carcinogenesis, we investigated the impact of EMX2 overexpression in glioma-related cell lines. Methods For that purpose, we constructed tetracycline-inducible EMX2 expression lines. Transfected cell phenotypes (proliferation, cell death and cell cycle) were assessed in time-course experiments. Results Restoration of EMX2 expression in U87 glioblastoma cells significantly inhibited cell proliferation. This inhibition was reversible after EMX2 removal from cells. EMX2-induced proliferative inhibition was very likely due to cell cycle arrest in G1/S transition and was not accompanied by signs of cell death. Conclusion Our results suggest that EMX2 may constitute a putative therapeutic target for GB treatment. Further studies are required to decipher the gene networks and transduction signals involved in EMX2’s effect on cell proliferation.
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- 2018
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8. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation
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Marion Maurel, Joanna Obacz, Tony Avril, Yong‐Ping Ding, Olga Papadodima, Xavier Treton, Fanny Daniel, Eleftherios Pilalis, Johanna Hörberg, Wenyang Hou, Marie‐Claude Beauchamp, Julien Tourneur‐Marsille, Dominique Cazals‐Hatem, Lucia Sommerova, Afshin Samali, Jan Tavernier, Roman Hrstka, Aurélien Dupont, Delphine Fessart, Frédéric Delom, Martin E Fernandez‐Zapico, Gregor Jansen, Leif A Eriksson, David Y Thomas, Loydie Jerome‐Majewska, Ted Hupp, Aristotelis Chatziioannou, Eric Chevet, and Eric Ogier‐Denis
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AGR2 ,endoplasmic reticulum ,inflammation ,proteostasis ,TMED2 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). Mouse AGR2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease (IBD). Although these biological effects are well established, the underlying molecular mechanisms of AGR2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR2 dimerization, we unveiled specific enhancers, including TMED2, and inhibitors of AGR2 dimerization, that control AGR2 functions. We demonstrate that modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.
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- 2019
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9. CD90/Thy-1, a Cancer-Associated Cell Surface Signaling Molecule
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Chloé Sauzay, Konstantinos Voutetakis, Aristotelis Chatziioannou, Eric Chevet, and Tony Avril
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THY-1 ,CD90 ,cancer ,invasion ,migration ,ER stress ,Biology (General) ,QH301-705.5 - Abstract
CD90 is a membrane GPI-anchored protein with one Ig V-type superfamily domain that was initially described in mouse T cells. Besides the specific expression pattern and functions of CD90 that were described in normal tissues, i.e., neurons, fibroblasts and T cells, increasing evidences are currently highlighting the possible involvement of CD90 in cancer. This review first provides a brief overview on CD90 gene, mRNA and protein features and then describes the established links between CD90 and cancer. Finally, we report newly uncovered functional connections between CD90 and endoplasmic reticulum (ER) stress signaling and discuss their potential impact on cancer development.
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- 2019
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10. Dual IRE1 RNase functions dictate glioblastoma development
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Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, Mari McMahon, Raphaël Pineau, Joanna Obacz, Olga Papadodima, Florence Jouan, Heloise Bourien, Marianthi Logotheti, Gwénaële Jégou, Néstor Pallares‐Lupon, Kathleen Schmit, Pierre‐Jean Le Reste, Amandine Etcheverry, Jean Mosser, Kim Barroso, Elodie Vauléon, Marion Maurel, Afshin Samali, John B Patterson, Olivier Pluquet, Claudio Hetz, Véronique Quillien, Aristotelis Chatziioannou, and Eric Chevet
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cancer ,endoplasmic reticulum ,IRE1 ,regulated IRE1‐dependent decay ,XBP1 ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1‐dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1‐dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
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- 2018
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11. Emerging Roles of the Endoplasmic Reticulum Associated Unfolded Protein Response in Cancer Cell Migration and Invasion
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Celia Maria Limia, Chloé Sauzay, Hery Urra, Claudio Hetz, Eric Chevet, and Tony Avril
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cancer ,cell invasion ,cell migration ,ER stress ,IRE1 ,PERK ,ATF6 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion.
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- 2019
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12. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties
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Delphine Fessart, Charlotte Domblides, Tony Avril, Leif A Eriksson, Hugues Begueret, Raphael Pineau, Camille Malrieux, Nathalie Dugot-Senant, Carlo Lucchesi, Eric Chevet, and Frederic Delom
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AGR2 ,cancer ,organoids ,protein disulphide isomerase ,endoplasmic reticulum ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.
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- 2016
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13. Immune genes are associated with human glioblastoma pathology and patient survival
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Vauléon Elodie, Tony Avril, Hamlat Abderrahmane, Etcheverry Amandine, Chiforeanu Dan, Menei Philippe, Mosser Jean, Quillien Véronique, and Aubry Marc
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Glioblastoma ,Immune system ,Survival ,Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults. Several recent transcriptomic studies in GBM have identified different signatures involving immune genes associated with GBM pathology, overall survival (OS) or response to treatment. Methods In order to clarify the immune signatures found in GBM, we performed a co-expression network analysis that grouped 791 immune-associated genes (IA genes) in large clusters using a combined dataset of 161 GBM specimens from published databases. We next studied IA genes associated with patient survival using 3 different statistical methods. We then developed a 6-IA gene risk predictor which stratified patients into two groups with statistically significantly different survivals. We validated this risk predictor on two other Affymetrix data series, on a local Agilent data series, and using RT-Q-PCR on a local series of GBM patients treated by standard chemo-radiation therapy. Results The co-expression network analysis of the immune genes disclosed 6 powerful modules identifying innate immune system and natural killer cells, myeloid cells and cytokine signatures. Two of these modules were significantly enriched in genes associated with OS. We also found 108 IA genes linked to the immune system significantly associated with OS in GBM patients. The 6-IA gene risk predictor successfully distinguished two groups of GBM patients with significantly different survival (OS low risk: 22.3 months versus high risk: 7.3 months; p Conclusions This study demonstrates the immune signatures found in previous GBM genomic analyses and suggests the involvement of immune cells in GBM biology. The robust 6-IA gene risk predictor should be helpful in establishing prognosis in GBM patients, in particular in those with a proneural GBM subtype, and even in the well-known good prognosis group of patients with methylated MGMT promoter-bearing tumors.
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- 2012
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14. Supplementary Materials and Methods, Supplementary Figures 1-7, Supplementary Tables 1-2 from CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
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Véronique Quillien, Eric Chevet, Jean Mosser, Anne Clavreul, Dan Cristian Chiforeanu, Elodie Vauléon, Jann N. Sarkaria, Paul A. Decker, Brett L. Carlson, Rivka R. Colen, Masumeh Hatami, Pierre-Jean Le Reste, Florence Jouan, Gwénaële Jegou, Joanna Obacz, Raphaël Pineau, Amandine Etcheverry, and Tony Avril
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Figure S1: CD90 mRNA expression on NCI and glioma cell lines, glioma and GBM specimens; Figure S2: CD90 mRNA and protein are expressed on all GBM cells; Figure S3: Expression of adhesion/migration genes in CD90low and CD90high RNS cell lines and EMT associated genes in CD90low and CD90high GBM patients; Figure S4: CD90 affects cell-cell/matrix adhesion of U251 and U87 GBM cell lines; Figure S5: CD90 affects migration of U251, U87 and primary GBM cell lines; Figure S6: CD90 signaling involves SRC and FAK kinases; Figure S7: CD90-dependent migration involves MEK1, Rac1 and JNK signaling molecules; TABLE S1: Patients demographic and clinical characteristics; TABLE S2: Top10 genes up-regulated in CD90low and CD90high GBM patients1.
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- 2023
15. Data from CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
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Véronique Quillien, Eric Chevet, Jean Mosser, Anne Clavreul, Dan Cristian Chiforeanu, Elodie Vauléon, Jann N. Sarkaria, Paul A. Decker, Brett L. Carlson, Rivka R. Colen, Masumeh Hatami, Pierre-Jean Le Reste, Florence Jouan, Gwénaële Jegou, Joanna Obacz, Raphaël Pineau, Amandine Etcheverry, and Tony Avril
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Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear.Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells.Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90high primary GSC lines.Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients. Clin Cancer Res; 23(23); 7360–74. ©2017 AACR.
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- 2023
16. A novel optinEuRin stress connection in glaucoma
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Elodie Lafont, Tony Avril, Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut National de la Santé et de la Recherche Médicale, Ligue Contre le Cancer, Région Bretagne, and Université de Rennes 1
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autophagy ,cell death ,glaucoma ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cell Biology ,ER stress ,Molecular Biology ,Biochemistry ,optineurin - Abstract
International audience; The endoplasmic reticulum (ER) is the organelle where the production and shaping of most secreted and transmembrane proteins happens. ER function is finely regulated to prevent accumulation of misfolded proteins generating ER stress. ER stress is common in both healthy and pathological situations due to multiple intrinsic and extrinsic factors including acute demand in protein synthesis, hypoxia or impaired protein folding caused by gene mutations. Sayyad et al. found that the M98K mutation of optineurin sensitizes glaucoma retinal ganglion cells to ER stress-induced cell death. This is associated with an autophagy-dependent elevation of ER stress sensor expression.
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- 2023
17. Author Reply to Peer Reviews of IRE1 RNase controls CD95-mediated cell death
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Diana Pelizzari-Raymundo, Raphael Pineau, Alexandra Papaioannou, Xingchen Zhou, Sophie Martin, Tony Avril, Matthieu Le Gallo, Eric Chevet, and Elodie Lafont
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- 2023
18. Challenges in glioblastoma research: focus on the tumor microenvironment
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Andreas Bikfalvi, Cristine Alves da Costa, Tony Avril, Jean-Vianney Barnier, Luc Bauchet, Lucie Brisson, Pierre Francois Cartron, Hélène Castel, Eric Chevet, Hervé Chneiweiss, Anne Clavreul, Bruno Constantin, Valérie Coronas, Thomas Daubon, Monique Dontenwill, Francois Ducray, Natacha Entz-Werlé, Dominique Figarella-Branger, Isabelle Fournier, Jean-Sébastien Frenel, Mathieu Gabut, Thierry Galli, Julie Gavard, Gilles Huberfeld, Jean-Philippe Hugnot, Ahmed Idbaih, Marie-Pierre Junier, Thomas Mathivet, Philippe Menei, David Meyronet, Céline Mirjolet, Fabrice Morin, Jean Mosser, Elisabeth Cohen-Jonathan Moyal, Véronique Rousseau, Michel Salzet, Marc Sanson, Giorgio Seano, Emeline Tabouret, Aurélie Tchoghandjian, Laurent Turchi, Francois M. Vallette, Somya Vats, Maité Verreault, Thierry Virolle, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Canaux et Connexines dans les Cancers et Cellules Souches (4CS), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), GHU Paris Psychiatrie et Neurosciences, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon, Departement de Neurologie (HCL), Equipe CADIR (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), ARC research grant ‘Fondation ARC’ 2018-2019 Role of PRL phosphatases in angiogenesis, Labellisation ARC ‘GliomaGuide’ (2018-2020), INCa PLBIO21-24, Ligue Contre le Cancer, Plan Cancer, Fondation ARC, ARTC, Cancéropôle Grand Sud Ouest to T.D., la Ligue Contre le Cancer (Comité Charente Maritime) to B.C. and VC, ARTC-sud to E.T., EU Transcan ERA Net Consortium grant ‘GliomaPRD’ (2018-2021), INCa PLBIO20-23 to T.D., E.C, Conseil Regional d’Aquitaine (2018-20019), Ligue Contre le Cancer (2017-2021) to A.B, INCa PLBIO17-220 to M.G, INCa PLBIO17-20 to E.C., Cancéropôle Grand-Ouest to E.C., F.V., J.G., and L.B., French Preclinical Brain Tumor Study Group ‘GrOupe Préclinique de l’Anocef’ (GOPA), figarella-branger, dominique, and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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[SDV] Life Sciences [q-bio] ,Cancer Research ,Oncology ,Invasion ,Tumor microenvironnement ,[SDV]Life Sciences [q-bio] ,Resistance to therapy ,Glioblastoma - Abstract
International audience; Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.
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- 2023
19. A novel blood brain barrier-permeable IRE1 kinase inhibitor for adjuvant glioblastoma treatment in mice
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Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Eric Chevet, Leif A. Eriksson, and Xavier Guillory
- Abstract
Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized the candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.
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- 2022
20. A novel blood brain barrier-permeable IRE1 kinase inhibitor sensitizes glioblastoma to chemotherapy in mice
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Diana Pelizzari-Raymundo, Dimitrios Doultsinos, Raphael Pineau, Chloé Sauzay, Thodoris Koutsandreas, Antonio Carlesso, Elena Gkotsi, Luc Negroni, Tony Avril, Aristotelis Chatziioannou, Xavier Guillory, Leif A. Eriksson, and Eric Chevet
- Abstract
Inositol Requiring Enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease. It is a major mediator of the Unfolded Protein Response (UPR), which is activated during endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues such as hypoxia or nutrient shortage and high metabolic/protein folding demand. To cope with those stresses, cancer cells utilize IRE1 signaling as an adaptive mechanism. Here we report the discovery of novel IRE1 inhibitors identified through a structural exploration of the IRE1 kinase domain. We first characterized these candidates in vitro and in cellular models. We showed that all molecules inhibit IRE1 signaling and sensitize glioblastoma cells to the standard chemotherapeutic temozolomide (TMZ). From these inhibitors, we retained a Blood-Brain Barrier (BBB) permeable molecule (Z4P) and demonstrated its ability to inhibit Glioblastoma (GB) growth and to prevent relapse in vivo when administered together with TMZ. These results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB. We thus satisfy an unmet need for targeted, non-toxic, IRE1 inhibitors as adjuvant therapeutic agents against GB.
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- 2022
21. The unfolded protein response as regulator of cancer stemness and differentiation: Mechanisms and implications for cancer therapy
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Mohammad Khoonkari, Frank A.E. Kruyt, Eric Chevet, Tony Avril, Dong Liang, University of Groningen [Groningen], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), DL was supported by the China Scholarship Council and the University of Groningen. MK was financially supported by the Zernike Institute for Advanced Materials at the University of Groningen, including funding from the Bonus Incentive Scheme (of the Dutch Ministry for Education, Culture and Science (OCW)). T. Avril was supported by La Ligue contre le cancer (comités 35, 56 and 85) and by l'Institut des Neurosciences Cliniques de Rennes (AAP 2020). EC was funded by Grants from Fondation pour la Recherche Médicale (FRM équipe labellisée 2018), Institut National du Cancer (INCa, PLBIO), Agence Nationale de la Recherche (ANR, ERAAT)., ANR-17-RAR3-0003,ERAAT,Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency(2017), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, and Enhancing Endoplasmic Reticulum Proteostasis to Rescue Alpha1 Antitrypsin Deficiency - - ERAAT2017 - ANR-17-RAR3-0003 - E-RARE - VALID
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PERK ,endocrine system ,Cell Survival ,medicine.medical_treatment ,Cellular homeostasis ,Antineoplastic Agents ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,IRE1 ,Biology ,Biochemistry ,Targeted therapy ,Unfolded protein response ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cancer stem cell ,Neoplasms ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,030304 developmental biology ,Pharmacology ,0303 health sciences ,ATF6 ,Cancer stem cells ,Cancer ,Cell Differentiation ,Tumor formation ,medicine.disease ,3. Good health ,Proteostasis ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,Therapy ,Stem cell - Abstract
International audience; The unfolded protein response (UPR) is an adaptive mechanism that regulates protein and cellular homeostasis. Three endoplasmic reticulum (ER) membrane localized stress sensors, IRE1, PERK and ATF6, coordinate the UPR in order to maintain ER proteostasis and cell survival, or induce cell death when homeostasis cannot be restored. However, recent studies have identified alternative functions for the UPR in developmental biology processes and cell fate decisions under both normal and cancerous conditions. In cancer, increasing evidence points towards the involvement of the three UPR sensors in oncogenic reprogramming and the regulation of tumor cells endowed with stem cell properties, named cancer stem cells (CSCs), that are considered to be the most malignant cells in tumors. Here we review the reported roles and underlying molecular mechanisms of the three UPR sensors in regulating stemness and differentiation, particularly in solid tumor cells, processes that have a major impact on tumor aggressiveness. Mainly PERK and IRE1 branches of the UPR were found to regulate CSCs and tumor development and examples are provided for breast cancer, colon cancer and aggressive brain tumors, glioblastoma. Although the underlying mechanisms and interactions between the different UPR branches in regulating stemness in cancer need to be further elucidated, we propose that PERK and IRE1 targeted therapy could inhibit self-renewal of CSCs or induce differentiation that is predicted to have therapeutic benefit. For this, more specific UPR modulators need to be developed with favorable pharmacological properties that together with patient stratification will allow optimal evaluation in clinical studies.
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- 2021
22. Death sentence: The tale of a fallen endoplasmic reticulum
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Eric Chevet, Elodie Lafont, Eoghan P. McGrath, Federica G. Centonze, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), This work was funded by grants from Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Médicale (FRM, équipe labellisée 2018), Agence Nationale de la Recherche (eRARE, eranet) to EC, and la Ligue Contre le Cancer (comités 35, 56 & 85 -AAP2019) to TA. EMG was funded by an Institut de Neurosciences Cliniques de Rennes (INCR) award. EL was supported by funds from the Fondation ARC and Fondation de France., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
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0301 basic medicine ,Cell death ,Programmed cell death ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Unfolded protein response ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Autophagy ,Pyroptosis ,Animals ,Humans ,Ferroptosis ,Molecular Biology ,Mechanism (biology) ,Endoplasmic reticulum ,Cell Biology ,Endoplasmic Reticulum Stress ,Cell biology ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Protein folding - Abstract
International audience; Endoplasmic Reticulum (ER) stress signaling is an adaptive mechanism triggered when protein folding demand overcomes the folding capacity of this compartment, thereby leading to the accumulation of improperly folded proteins. This stress signaling pathway is named the Unfolded Protein Response (UPR) and aims at restoring ER homeostasis. However, if this fails, mechanisms orienting cells towards death processes are initiated. Herein, we summarize the most recent findings connecting ER stress and the UPR with identified death mechanisms including apoptosis, necrosis, pyroptosis, ferroptosis, and autophagy. We highlight new avenues that could be investigated and controlled through actionable mechanisms in physiology and pathology.
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- 2021
23. SARS-CoV2 envelop proteins reshape the serological responses of COVID-19 patients
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Matthieu Le Gallo, Vincent Thibault, Florence Godey, Gwénaële Jégou, Christopher Heslan, Tony Avril, Eric Chevet, Leif A. Eriksson, and Sophie Martin
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Coronavirus disease 2019 (COVID-19) ,Myeloma protein ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Cancer ,Disease ,Biology ,medicine.disease ,medicine.disease_cause ,Virology ,Serology ,Immune system ,Membrane protein ,medicine ,Coronavirus - Abstract
The SARS-CoV-2 pandemic has elicited a unique international mobilization of the scientific community to better understand this coronavirus and its associated disease and to develop efficient tools to combat infection. Similar to other coronavirae, SARS-CoV-2 hijacks the host cell complex secretory machinery to produce properly folded viral proteins that will compose the nascent virions; including Spike, Envelope and Membrane proteins, the most exposed membrane viral proteins to the host immune system. Antibody response is part of the anti- viral immune arsenal that infected patients develop to fight viral particles in the body. Herein, we investigate the immunogenic potential of Spike (S), Envelope (E) and Membrane (M) proteins using a human cell-based system to mimic membrane insertion and N-glycosylation. We show that both S and M proteins elicit the production of specific IgG, IgM and IgA in SARS- CoV-2 infected patients. Elevated Ig responses were observed in COVID+ patients with moderate and severe forms of the disease. Finally, when SARS-CoV-2 Spike D614 and G614 variants were compared, reduced Ig binding was observed with the Spike G614 variant. Altogether, this study underlines the needs for including topological features in envelop proteins to better characterize the serological status of COVID+ patients, points towards an unexpected immune response against the M protein and shows that our assay could represent a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness. Funding: This work was funded by grants from INSERM, Institut National du Cancer (INCa PLBIO), Fondation pour la Recherche Medicale (FRM, equipe labellisee 2018) to EC and from la Ligue contre le cancer (comite 35, 56 et 85) to TA. Conflict of Interest: EC and LAE are founders of Cell Stress Discoveries Ltd. Ethical Approval: The study was carried out according to the regulation of Rennes Biobank (BRIF number: BB-0033-00056) certified as meeting the requirements of NF S96900 for receipt preparation preservation and provision of biological resources.
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- 2021
24. IRE1-mediated miRNA maturation in macrophage phosphoinositide signaling
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Eric Chevet, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut National du Cancer (INCa PLBIO) Institut National du Cancer (INCA) France, Agence Nationale de la Recherche (ANR) French National Research Agency (ANR), Fondation pour la Recherche Medicale (FRM, equipe labellisee 2018), la Ligue Contre le Cancer (comites 35) [56 85-AAP2019], Agence Nationale de la Recherche (IRE1inNASH)French National Research Agency (ANR), Agence Nationale de la Recherche (eRANET eRARE-ERAAT) French National Research Agency (ANR), ANR-18-CE14-0022,IRE1inNASH,Cibler la voie IRE1 dans la stéatohépatite(2018), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Jonchère, Laurent, and APPEL À PROJETS GÉNÉRIQUE 2018 - Cibler la voie IRE1 dans la stéatohépatite - - IRE1inNASH2018 - ANR-18-CE14-0022 - AAPG2018 - VALID
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RNase P ,Endoribonuclease ,Inflammation ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Protein Serine-Threonine Kinases ,Phosphatidylinositols ,Biochemistry ,03 medical and health sciences ,Endonuclease ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Endoribonucleases ,microRNA ,Genetics ,medicine ,Humans ,News & Views ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,biology ,Macrophages ,Endoplasmic reticulum ,Endoplasmic Reticulum Stress ,Cell biology ,Unfolded Protein Response ,biology.protein ,Unfolded protein response ,medicine.symptom ,Inositol ,030217 neurology & neurosurgery ,Dicer - Abstract
The ER-bound kinase/endoribonuclease (RNase), inositol-requiring enzyme-1 (IRE1), regulates the phylogenetically most conserved arm of the unfolded protein response (UPR). However, the complex biology and pathology regulated by mammalian IRE1 cannot be fully explained by IRE1's one known, specific RNA target, X box-binding protein-1 (XBP1) or the RNA substrates of IRE1-dependent RNA degradation (RIDD) activity. Investigating other specific substrates of IRE1 kinase and RNase activities may illuminate how it performs these diverse functions in mammalian cells. We report that macrophage IRE1 plays an unprecedented role in regulating phosphatidylinositide-derived signaling lipid metabolites and has profound impact on the downstream signaling mediated by the mammalian target of rapamycin (mTOR). This cross-talk between UPR and mTOR pathways occurs through the unconventional maturation of microRNA (miR) 2137 by IRE1's RNase activity. Furthermore, phosphatidylinositol (3,4,5) phosphate (PI(3,4,5)P
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- 2020
25. Author Reply to Peer Reviews of Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells
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Eric Chevet, Tony Avril, Véronique Quillien, Aristotelis Chatziioannou, Luc Négroni, Qinping Zheng, John Patterson, Abhay Pandit, Juhi Samal, Boaz Tirosh, Zvi Granot, Akram Obiedat, Tanya Fainsod-Levi, Konstantinos Voutetakis, Efstathios Vlachavas, Kim Barroso, Sophie Martin, Raphael Pineau, Pierre Jean Le Reste, Daria Sicari, Jérôme Archambeau, and Joanna Obacz
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- 2020
26. Development of a novel preclinical glioblastoma mouse model and therapeutic impact of IRE1 inhibition
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Pierre Jean Le Reste, Raphael Pineau, Konstantinos Voutetakis, Juhi Samal, Gwénaële Jégou, Stéphanie Lhomond, Adrienne M. Gorman, Afshin Samali, John B Patterson, Qingping Zeng, Abhay Pandit, Marc Aubry, Nicolas Soriano, Amandine Etcheverry, Aristotelis Chatziioannou, Jean Mosser, Tony Avril, and Eric Chevet
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- 2020
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27. Local intracerebral inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo
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Qingping Zeng, Raphael Pineau, Pierre-Jean Le Reste, Afshin Samali, Amandine Etcheverry, Adrienne M. Gorman, Juhi Samal, Aristotelis Chatziioannou, Jean Mosser, Nicolas Soriano, Eric Chevet, Marc Aubry, Stéphanie Lhomond, Gwénaële Jégou, John B. Patterson, Tony Avril, Konstantinos Voutetakis, Abhay Pandit, Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), CRLCC Eugène Marquis (CRLCC), Rennes Brain Cancer Team (REACT), University of Thessaly [Volos] (UTH), National University of Ireland [Galway] (NUI Galway), Fosun Orinove PharmaTech Inc.[Newbury Park, CA], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), CHU Pontchaillou [Rennes], National Hellenic Research Foundation [Athens], Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was funded by grants from the French National Cancer Institute (INCa, PLBIO2017, 2019, 2020), the Fondation pour la recherche Médicale (FRM, équipe labellisée 2018) to EC and EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) grants to AS, AC and EC. The work was also supported in part by research grant from Science Foundation Ireland (SFI), co-funded under the European Regional Development Fund under Grant number 13/RC/2073., BIOSIT H2P2 platform, BIOSIT Animal facility ARCHE (https://biosit.univ-rennes1.fr/), European Project: 675448,H2020,H2020-MSCA-ITN-2015,TRAIN-ERS(2015), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_treatment ,Disease ,Injections, Intralesional ,Mice ,0302 clinical medicine ,Tumor Microenvironment ,0303 health sciences ,Stress sensor ,Brain Neoplasms ,Combined Modality Therapy ,Chemotherapy regimen ,Neoadjuvant Therapy ,Treatment efficacy ,3. Good health ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,030220 oncology & carcinogenesis ,Immunocompetence ,Craniotomy ,medicine.medical_specialty ,Morpholines ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,IRE1 ,03 medical and health sciences ,Animal model ,Drug Therapy ,In vivo ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Humans ,Benzopyrans ,030304 developmental biology ,Chemotherapy ,Radiotherapy ,business.industry ,Gene Expression Profiling ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Unfolded protein response ,Unfolded Protein Response ,Tumor surgery ,business ,Glioblastoma ,Endoplasmic reticulum - Abstract
Glioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy patient’s survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed a novel immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.
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- 2020
28. Extracellular AGR3 regulates breast cancer cells migration via Src signaling
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Silvia Pastorekova, Joanna Obacz, Daria Sicari, Michal Durech, Frédéric Delom, Lucia Sommerova, Filippo Iuliano, Eric Chevet, Delphine Fessart, Tony Avril, Roman Hrstka, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Masaryk Memorial Cancer Institute (RECAMO), Slovak Academy of Sciences (SAS), CRLCC Eugène Marquis (CRLCC), Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Institut Bergonié [Bordeaux], UNICANCER, Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Masaryk Memorial Cancer Institute (MMCI), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
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0301 basic medicine ,Cancer Research ,medicine.drug_class ,AGR2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Src family kinases ,migration ,03 medical and health sciences ,Src phosphorylation ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Extracellular ,medicine ,cancer ,anterior gradient proteins ,Oncogene ,Chemistry ,Kinase ,Articles ,Protein kinase inhibitor ,Cell cycle ,Dasatinib ,adhesion ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,secreted protein disulfide isomerase family ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
International audience; Human anterior gradient proteins AGR2 and AGR3 are overexpressed in a variety of adenocarcinomas and are often secreted in cancer patients' specimens, which suggests a role for AGR proteins in intra and extracellular compartments. Although these proteins exhibit high sequence homology, AGR2 is predominantly described as a pro-oncogene and a potential prognostic biomarker. However, little is known about the function of AGR3. Therefore, the aim of the present study was to investigate the role of AGR3 in breast cancer. The results demonstrated that breast cancer cells secrete AGR3. Furthermore, it was revealed that extracellular AGR3 (eAGR3) regulates tumor cell adhesion and migration. The current study indicated that the pharmacological and genetic perturbation of Src kinase signaling, through treatment with Dasatinib (protein kinase inhibitor) or investigating cells that express a dominant-negative form of Src, significantly abrogated eAGR3-mediated breast cancer cell migration. Therefore, the results indicated that eAGR3 may control tumor cell migration via activation of Src kinases. The results of the present study indicated that eAGR3 may serve as a microenvironmental signaling molecule in tumor-associated processes.
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- 2019
29. SARS-CoV-2 integral membrane proteins shape the serological responses of patients with COVID-19
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Vincent Thibault, Leif A. Eriksson, Gwénaële Jégou, Tony Avril, Eric Chevet, Florence Godey, Matthieu Le Gallo, Christopher Heslan, and Sophie Martin
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0303 health sciences ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,Membrane insertion ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Science ,viruses ,Immunology ,Biology ,biochemical phenomena, metabolism, and nutrition ,Virology ,Transmembrane protein ,Article ,3. Good health ,Serology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,In patient ,Integral membrane protein ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat the infection. Like other coronavirae, SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including spike (S), envelope (E), and membrane (M) proteins, the most exposed transmembrane proteins to the host immune system. As antibody response is part of the anti-viral immune arsenal, we investigate the immunogenic potential of S, E, and M using a human cell-based system to mimic membrane insertion and N-glycosylation. Both S and M elicit specific Ig production in patients with SARS-CoV-2. Patients with moderate and severe diseases exhibit elevated Ig responses. Finally, reduced Ig binding was observed with spike G614 compared to D614 variant. Altogether, our assay points toward an unexpected immune response against M and represents a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness., Graphical abstract, Immunology; Virology
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- 2021
30. P11.61 Development of a novel preclinical GBM model and therapeutic impact of IRE1 inhibition
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Raphael Pineau, John B. Patterson, Gwénaële Jégou, F Jouan, Tony Avril, Elodie Vauleon, P. J. Le Reste, Eric Chevet, Juhi Samal, Abhay Pandit, CHU Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Cancer Research ,business.industry ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,3. Good health ,Poster Presentations ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,Neurology (clinical) ,business ,030217 neurology & neurosurgery - Abstract
Glioblastoma Multiforme (GBM) is the most severe primary brain tumor and represents more than 15% of all brain tumors. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy, patient’s survival post diagnosis remains short with a median overall survival of 15 months. The lack of efficacy of the current treatments is mostly due to the tumor heterogeneity with different tumor cell types that exhibit various sensitivity to anti-cancer agents and to the diffuse feature of GBM that complicates the efficacy of complete resection. Another limitation for finding new valuable therapy approaches is the lack of relevant animal models that extensively recapitulate the current GBM patients’ standard of care. In the past couple of years, it has been demonstrated that the Unfolded Protein Response (UPR) plays an instrumental role in GBM development. It has been shown that IRE1, the most conserved UPR sensor, signals in tumor cells to reshape the tumor microenvironment to favor tumor growth and most likely to alter the response to treatment. The IRE1/XBP1s signaling axis exhibits pro-oncogenic properties and has a direct impact on patients’ survival. These observations point toward the IRE1/XBP1s axis as a potentially relevant therapeutic target. To further test the potential impact of the pharmacological targeting IRE1/XBP1 signaling, we proposed to use MKC8866, an inhibitors of IRE1, in preclinical models of GBM. As such we developed a novel GBM animal model that recapitulates the different steps engaged in GBM patient clinical handling (including surgical resection, irradiation and chemotherapy), and use this to demonstrate the relevance of IRE1 inhibition in GBM. Considering that IRE1 inhibitors do not cross the blood-brain barrier, we proposed an intraoperative delivery of the drugs though fibrin glue plugs applicated within the resection cavity, and then studied the impact on survival and tumor microenvironment. We showed that local delivery of IRE1 inhibitors combined with radio/chemotherapy had a positive effect on survival and induced tumoral and microenvironment remodeling, pointing at its high therapeutic potential and the need for an early clinical trial.
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- 2019
31. Stress signaling in pain control
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Tony Avril, Eric Chevet, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), ERANET ANR (ERAAT), Institut National du Cancer (INCa), Fondation pour la Recherche Medicale (FRM), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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X-Box Binding Protein 1 ,Pain ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Protein Serine-Threonine Kinases ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Endoribonucleases ,Pain control ,Leukocytes ,Humans ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Protein-Serine-Threonine Kinases ,business.industry ,Stress signaling ,fungi ,food and beverages ,Prostaglandins ,business ,030217 neurology & neurosurgery - Abstract
Endoplasmic reticulum stress can drive chronic pain, revealing a new target
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- 2019
32. The integrated stress response promotes B7H6 expression
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Noam Stern-Ginossar, Ofer Mandelboim, Einat Seidel, Lorraine Springuel, Julie Tai-Schmiedel, Boaz Tirosh, Eric Chevet, Miriam Shmuel, David E. Gilham, Mohamed Mahameed, Akram Obiedat, Yoav Charpak-Amikam, Tony Avril, Priya Dipta, Jennifer Bolsée, The Hebrew University of Jerusalem (HUJ), The Hebrew University Hadassah Medical School, Weizmann Institute of Science [Rehovot, Israël], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), 0, Ministry of Science and Technology, Israel, 721236, H2020 Marie Skłodowska-Curie Actions, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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PERK ,B7 Antigens ,T-Lymphocytes ,Eukaryotic Initiation Factor-2 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Blood Donors ,UPR ,Transfection ,Immunotherapy, Adoptive ,Lopinavir ,03 medical and health sciences ,eIF-2 Kinase ,0302 clinical medicine ,Downregulation and upregulation ,Transduction, Genetic ,Cell Line, Tumor ,Drug Discovery ,medicine ,HIV Protease Inhibitor ,Integrated stress response ,Humans ,Phosphorylation ,Protein kinase A ,B7H6 ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Nelfinavir ,Receptors, Chimeric Antigen ,Kinase ,Chemistry ,Endoplasmic reticulum ,HIV Protease Inhibitors ,Endoplasmic Reticulum Stress ,3. Good health ,Cell biology ,CAR-T ,Killer Cells, Natural ,030220 oncology & carcinogenesis ,Unfolded protein response ,Unfolded Protein Response ,Molecular Medicine ,Original Article ,medicine.drug ,Signal Transduction - Abstract
Abstract The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CAR-T cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy. Key messages B7H6 is induced by ER stress in a PERK-dependent mechanism. Induction of B7H6 is obtained pharmacologically by HIV protease inhibitors. Exposure of tumor cells to the HIV protease inhibitor nelfinavir improves the recognition by B7H6-directed CAR-T.
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- 2019
33. Constitutive UPRER activation sustains tumor cell differentiation
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Qingping Zheng, Tony Avril, Joanna Obacz, Raphael Pineau, Akram Obiedat, Juhi Samal, Aristotelis Chatziioannou, Mari McMahon, Konstantinos Voutetakis, Afshin Samali, Eric Chevet, John B. Patterson, Abhay Pandit, Boaz Tirosh, Le Reste P, and Dimitrios Doultsinos
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0303 health sciences ,XBP1 ,Cell ,Biology ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Proteostasis ,medicine.anatomical_structure ,SOX2 ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Unfolded protein response ,Reprogramming ,Transcription factor ,030304 developmental biology - Abstract
Endoplasmic Reticulum (ER) proteostasis control and the Unfolded Protein Response (UPRER) have been shown to contribute to tumor development and aggressiveness. As such, the UPRERsensor IRE1α (referred to as IRE1 hereafter) is a major regulator of glioblastoma (GBM) development and is an appealing therapeutic target. To document IRE1 suitability as an antineoplastic pharmacological target, we investigated how this protein contributed to GBM cell reprogramming, a property involved in treatment resistance and disease recurrence. Probing the IRE1 activity molecular signature on transcriptome datasets of human tumors, showed that high IRE1 activity correlated with low expression of the main GBM stemness transcription factors SOX2, SALL2, POU3F2 and OLIG2. Henceforth, this phenotype was pharmacologically and genetically recapitulated in immortalized and primary GBM cell lines as well as in mouse models. We demonstrated that constitutive activation of the IRE1/XBP1/miR148a signaling axis repressed the expression of SOX2 and led to maintenance of a differentiation phenotype in GBM cells. Our results describe a novel role for IRE1 signaling in maintaining differentiated tumor cell state and highlight opportunities of informed IRE1 modulation utility in GBM therapy.
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- 2019
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34. Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients
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Elodie Vauleon, Alain Gey, Antoine F. Carpentier, Véronique Quillien, Boris Campillo-Gimenez, Eric Tartour, Tony Avril, Floraly Sejalon, Centre Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), angiogenesis and tumour grant, Roche, Jonchère, Laurent, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,medicine.drug_class ,Neutrophils ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Kaplan-Meier Estimate ,Gastroenterology ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,Basal (phylogenetics) ,Leukocyte Count ,0302 clinical medicine ,Immune system ,Antineoplastic Agents, Immunological ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Prospective Studies ,Aged ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Complete blood count ,Retrospective cohort study ,Regulatory T cells ,Biomarker ,Middle Aged ,3. Good health ,Clinical trial ,Regimen ,Oncology ,Corticosteroid ,Original Article ,Female ,Neoplasm Recurrence, Local ,business ,Glioblastoma ,030215 immunology ,medicine.drug - Abstract
Bevacizumab (Bv) remains frequently prescribed in glioblastoma (GBM) patients, especially at recurrence. We conducted a prospective clinical trial with 29 recurrent GBM patients treated with Bv alone with a longitudinal follow-up of different circulating immune cells [complete blood count, myeloid-derived suppressor cells (MDSCs), classical, intermediate, non-classical and Tie2 monocytes, VEGFR1+ and regulatory T cells (Treg)]. We observed a significant increase for leucocytes, neutrophils, eosinophils and classical monocytes and a decrease for the fraction of Treg during the treatment. The best prognostic values for survival under Bv were obtained for basal neutrophils and Treg. Counts below 3.9 G/L for neutrophils and above 0.011 G/L for Treg were associated with an overall survival of 17.5 and 19.9 months, respectively, as compared with 5.4 and 5.6 months, respectively, for counts above and below these cutoffs (p = 0.004 and p
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- 2019
35. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1
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Mohamed Mahameed, Mari McMahon, Konstantinos Voutetakis, Akram Obiedat, Eric Chevet, Orit Berhani, Einat Seidel, Boaz Tirosh, Pinchas Tsukerman, Aristotelis Chatziioannou, Tony Avril, Ofer Mandelboim, The Hebrew University of Jerusalem (HUJ), University of Thessaly [Volos] (UTH), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), National University of Ireland Maynooth (Maynooth University), CRLCC Eugène Marquis (CRLCC), Ministry of Science and Technology, Israel, Ministère des Affaires Étrangères, Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, David R. Bloom Center for Pharmacy, Hebrew University of Jerusalem, Israel Cancer Association USA, 696/14, Israel Science Foundation, Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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X-Box Binding Protein 1 ,0301 basic medicine ,endocrine system ,XBP1 ,Transcription, Genetic ,medicine.medical_treatment ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,NK cells ,UPR ,Protein Serine-Threonine Kinases ,Endoplasmic Reticulum ,Ligands ,environment and public health ,digestive system ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,Cell Line, Tumor ,Endoribonucleases ,Genetics ,medicine ,Humans ,E2F1 ,RNA, Messenger ,Molecular Biology ,Effector ,Chemistry ,Endoplasmic reticulum ,Histocompatibility Antigens Class I ,fungi ,Immunotherapy ,Endoplasmic Reticulum Stress ,Cell biology ,stomatognathic diseases ,030104 developmental biology ,NK Cell Lectin-Like Receptor Subfamily K ,biological sciences ,Unfolded Protein Response ,Unfolded protein response ,immunotherapy ,Signal transduction ,biological phenomena, cell phenomena, and immunity ,ER stress ,E2F1 Transcription Factor ,030217 neurology & neurosurgery ,Signal Transduction ,Transcription Factors ,Biotechnology - Abstract
International audience; The unfolded protein response (UPR) is an adaptive signaling pathway activated in response to endoplasmic reticulum (ER) stress. The effectors of the UPR are potent transcription activators; however, some genes are suppressed by ER stress at the mRNA level. The mechanisms underlying UPR-mediated gene suppression are less known. Exploration of the effect of UPR on NK cells ligand expression found that the transcription of NK group 2 member D (NKG2D) ligand major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) is suppressed by the inositol-requiring enzyme 1 (IRE1)/X-box binding protein 1 (XBP1) pathway of the UPR. Deletion of IRE1 or XBP1 was sufficient to promote mRNA and surface levels of MICA. Accordingly, NKG2D played a greater role in the killing of IRE1/XBP1 knockout target cells. Analysis of effectors downstream to XBP1s identified E2F transcription factor 1 (E2F1) as linking UPR and MICA transcription. The inverse correlation between XBP1 and E2F1 or MICA expression was corroborated in RNA-Seq analysis of 470 primary melanoma tumors. While mechanisms that connect XBP1 to E2F1 are not fully understood, we implicate a few microRNA molecules that are modulated by ER stress and possess dual suppression of E2F1 and MICA. Because of the importance of E2F1 and MICA in cancer progression and recognition, these observations could be exploited for cancer therapy by manipulating the UPR in tumor cells.-Obiedat, A., Seidel, E., Mahameed, M., Berhani, O., Tsukerman, P., Voutetakis, K., Chatziioannou, A., McMahon, M., Avril, T., Chevet, E., Mandelboim, O., Tirosh, B. Transcription of the NKG2D ligand MICA is suppressed by the IRE1/XBP1 pathway of the unfolded protein response through the regulation of E2F1.
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- 2019
36. Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells
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Joanna Obacz, Jérôme Archambeau, Daria Sicari, Pierre Jean Le Reste, Raphael Pineau, Sophie Martin, Kim Barroso, Efstathios Vlachavas, Konstantinos Voutetakis, Tanya Fainsod-Levi, Akram Obiedat, Zvi Granot, Boaz Tirosh, Juhi Samal, Abhay Pandit, John Patterson, Qinping Zheng, Luc Négroni, Aristotelis Chatziioannou, Véronique Quillien, Tony Avril, and Eric Chevet
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0303 health sciences ,Chemokine ,XBP1 ,biology ,Angiogenesis ,Endoplasmic reticulum ,Inflammation ,3. Good health ,03 medical and health sciences ,CXCL2 ,0302 clinical medicine ,Tumor progression ,030220 oncology & carcinogenesis ,Unfolded protein response ,Cancer research ,medicine ,biology.protein ,medicine.symptom ,030304 developmental biology - Abstract
Many intrinsic and environmental stresses trigger the accumulation of misfolded proteins in the endoplasmic reticulum (ER), leading to ER stress. This condition has been observed in various human diseases, including cancer. As such, glioblastoma multiforme (GBM), the most aggressive and lethal primary brain tumor, was reported to present features of ER stress and to depend on ER stress signaling to sustain growth. Tumor cells can also use unfolded protein response (UPR) signaling to acquire malignant features thereby promoting tumor progression. IRE1 is a central mediator of the UPR, whose RNase activity leads to the non-conventional splicing of XBP1 mRNA and RNA degradation through Regulated IRE1 dependent decay (RIDD). We recently showed that IRE1 activity in GBM promotes tumor invasion, angiogenesis and infiltration by macrophages. Hence, high tumor IRE1 activity predicted worse outcome in vivo. Herein, we further characterize the IRE1-dependent signaling mechanism that shapes the brain tumor immune microenvironment, in particular towards myeloid cells. The latter phenomenon is mediated in part by IRE1-dependent regulation of CXCL2, IL6 and IL8 expression. We further found that IRE1 through the XBP1s transcriptional activity induces the expression of E2 ubiquitin enzyme UBE2D3, which in turn promotes inflammation. We show that UBE2D3 triggers the recruitment of myeloid cells to tumors in vitro and in vivo by targeting the NFKB signaling inhibitor, IKB leading to the up-regulation of pro-inflammatory chemokines expression. Our work identifies a novel IRE1/UBE2D3 signaling axis that plays an instrumental role in the immune regulation of glioblastoma.
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- 2019
37. Control of glioblastoma differentiated-to-stem cell reprogramming by IRElα/XBPls signaling
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Dimitrios Doultsinos, Mari McMahon, Konstantinos Voutetakis, Joanna Obacz, Raphael Pineau, Florence Jouan, Pierre-Jean Le Reste, Akram Obiedat, Juhi Samal, John B. Patterson, Qingping Zheng, Afshin Samali, Abhay Pandit, Boaz Tirosh, Aristotelis Chatziioannou, View ORCID ProfileEric Chevet, and Tony Avril
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- 2019
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38. Regulation of tumor-stroma interactions by the unfolded protein response
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Aeid Igbaria, Jozef P. Bossowski, Jean-Ehrland Ricci, Eric Chevet, Camila Rubio-Patiño, Joanna Obacz, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), University of California [San Francisco] (UC San Francisco), University of California (UC), This work was funded by grants from Institut National du Cancer (INCa, PLBIO: 2017, PLBIO: 2015- 111, INCA_7981), and Ligue Contre le Cancer, EU H2020 MSCA ITN-675448 (TRAINERS) and MSCA RISE-734749 (INSPIRED) to EC, Fondation ARC pour la Recherche sur le Cancer and the Agence Nationale de la Recherche (LABEX SIGNALIFE ANR-11-LABX-0028-01) to JER, Juvenile diabetes research foundation (JDRF 3-PDF-2015-80-A-N) to AI., ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), Chemistry, Oncogenesis, Stress and Signaling ( COSS ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CRLCC Eugène Marquis ( CRLCC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CRLCC Eugène Marquis ( CRLCC ), Centre méditérannéen de médecine moléculaire ( C3M ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), University of California [San Francisco] (UCSF), and University of California
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0301 basic medicine ,Stromal cell ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Endoplasmic Reticulum ,Biochemistry ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neoplasms ,immunogenic cell death ,Animals ,Humans ,tumor microenvironment ,Molecular Biology ,Tumor microenvironment ,Endoplasmic reticulum ,Cell Biology ,unfolded protein response ,Endoplasmic Reticulum Stress ,Cell biology ,Crosstalk (biology) ,030104 developmental biology ,inflammation ,030220 oncology & carcinogenesis ,Unfolded protein response ,Immunogenic cell death ,Protein folding ,Stromal Cells ,ER stress - Abstract
International audience; The unfolded protein response (UPR) is a conserved adaptive pathway that helps cells cope with the protein misfolding burden within the endoplasmic reticulum (ER). Imbalance between protein folding demand and capacity in the ER leads to a situation called ER stress that is often observed in highly proliferative and secretory tumor cells. As such, activation of the UPR signaling has emerged as a key adaptive mechanism promoting cancer progression. It is becoming widely acknowledged that, in addition to its intrinsic effect on tumor biology, the UPR can also regulate tumor microenvironment. In this review, we discuss how the UPR coordinates the crosstalk between tumor and stromal cells, such as endothelial cells, normal parenchymal cells, and immune cells. In addition, we further describe the involvement of ER stress signaling in the response to current treatments as well as its impact on antitumor immunity mainly driven by immunogenic cell death. Finally, in this context, we discuss the relevance of targeting ER stress/UPR signaling as a potential anticancer approach.
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- 2019
39. Alterations of EDEM1 functions enhance ATF6 pro-survival signaling
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Eric Chevet, Gwénaële Jégou, Laure Saas, Florence Jouan, Raphael Pineau, Tony Avril, Arisa Higa, Olivier Pluquet, Alexandra Papaioannou, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Equipe Labellisée 2018, La Fondation pour la Recherche Médicale, ITN-675448, EU H2020 MSCA, INCa_7981, Institut National du Cancer, INCa_5869, Institut National du Cancer, INCa_PLBIO_ 2015-111, Institut National du Cancer, ICGC0, Institut National du Cancer, INCa_PLBIO_2017, Institut National du Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
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0301 basic medicine ,Proteases ,Carcinoma, Hepatocellular ,Activating transcription factor ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biochemistry ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Transcription (biology) ,Tumor Cells, Cultured ,Gene silencing ,Humans ,cancer ,Molecular Biology ,Cell Proliferation ,Chemistry ,ATF6 ,Endoplasmic reticulum ,Liver Neoplasms ,Membrane Proteins ,Cell Biology ,unfolded protein response ,Golgi apparatus ,Endoplasmic Reticulum Stress ,Cell biology ,Activating Transcription Factor 6 ,030104 developmental biology ,030220 oncology & carcinogenesis ,endoplasmic reticulum quality control ,Mutation ,symbols ,Unfolded protein response ,Signal Transduction - Abstract
International audience; Activating transcription factor 6 alpha (referred to as ATF6 hereafter) is an endoplasmic reticulum (ER)-resident glycoprotein and one of the three sensors of the unfolded protein response (UPR). Upon ER stress, ATF6 is exported to the Golgi complex where it is cleaved by the S1P and S2P proteases thus releasing ATF6 cytosolic fragment and leading to the transcription of ATF6 target genes. In this study, we performed a phenotypic small-interfering RNA (siRNA) screening to better characterize the ER mechanisms involved in ATF6 activation upon ER stress. This revealed that silencing of ER-degradation-enhancing alpha-mannosidase-like protein-1 (EDEM1) increased the bioavailability of ER stress-induced ATF6 export to the Golgi complex through the stabilization of the natively unstable ATF6 protein. Moreover, we characterized a somatic variant of EDEM1 (N198I) found in hepatocellular carcinoma that alters ATF6 signaling and might provide a selective advantage to the transforming cells. Hence, our work confirms the natively unstable nature of ATF6 and links this property to potentially associated pro-oncogenic functions.
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- 2018
40. Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance
- Author
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Konstantinos Voutetakis, Els Verhoeyen, Jean-Ehrland Ricci, Laura Mondragón, Cynthia Lebeaupin, Jozef P. Bossowski, Camila Rubio-Patiño, Aristotelis Chatziioannou, François Fenaille, Eric Chevet, Johanna Chiche, Thierry Passeron, Lazaro Emilio Aira, Tony Avril, Gian Marco De Donatis, Sandrine Marchetti, Rana Mhaidly, Florence Castelli, John B. Patterson, Patricia Lamourette, Elodie Villa, Emeline Chu-Van, Béatrice Bailly-Maitre, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), MetaboHUB, Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Chemistry, Oncogenesis, Stress and Signaling (COSS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Canceropôle PACA, Fondation pour la Recherche Médicale, La Ligue contre le Cancer, EU H2020, Agence Nationale de la Recherche, Ligue Contre le Cancer, Commissariat à l'Énergie Atomique et aux Énergies Alternatives, Association Française pour l'Etude du Foie, Institut National de la Santé et de la Recherche Médicale, Société Francophone du Diabète, Fondation ARC pour la Recherche sur le Cancer, INCa PLBIO: 2015-111, Institut National Du Cancer, Institut National du Cancer and Conseil Régional PACA, French Ministry of Research, ANR-11-INBS-0010, MetaboHUB, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011)
- Subjects
0301 basic medicine ,Lymphoma ,Physiology ,medicine.medical_treatment ,Melanoma, Experimental ,immunosurveillance ,UPR ,CD8-Positive T-Lymphocytes ,anti-tumor immunity ,Mice ,Immunologic Surveillance ,Mice, Inbred BALB C ,3. Good health ,Immunosurveillance ,Cytokine ,RIG1 ,Female ,Colorectal Neoplasms ,ER stress ,RNA Helicases ,Signal Transduction ,Antigen-Presenting Cells ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Protein Serine-Threonine Kinases ,Biology ,Lymphocyte Depletion ,03 medical and health sciences ,Immune system ,Low-protein diet ,Cell Line, Tumor ,Endoribonucleases ,Diet, Protein-Restricted ,medicine ,Animals ,cancer ,[CHIM]Chemical Sciences ,Molecular Biology ,Cancer ,dietary restriction ,Neoplasms, Experimental ,Cell Biology ,IRE1α ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,Cancer cell ,Unfolded Protein Response ,Unfolded protein response ,Cancer research ,diet ,CD8 - Abstract
International audience; Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.
- Published
- 2018
41. CD90 Expression Controls Migration and Predicts Dasatinib Response in Glioblastoma
- Author
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Dan Cristian Chiforeanu, Anne Clavreul, Jann N. Sarkaria, Tony Avril, Masumeh Hatami, Eric Chevet, Rivka R. Colen, Raphael Pineau, Paul A. Decker, Pierre-Jean Le Reste, Véronique Quillien, Amandine Etcheverry, Brett L. Carlson, Gwénaële Jégou, Elodie Vauleon, Florence Jouan, Jean Mosser, Joanna Obacz, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Eugène Marquis (CRLCC), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), la Ligue Contre le Cancer Comite d'Ille-et-Villaine, d'Indre-et-Loire et du Morbihan, Region Bretagne AAP CRITT sante, Aidez la recherche! from the Centre Eugene Marquis, la Ligue Contre le Cancer Comite des Landes (LARGE project), l'Institut National du Cancer [INCa_5869, INCa_7981, PLBIO: 2015-111], EU H2020 MSCA (TRAINERS) [ITN-675448], Jonchère, Laurent, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
- Subjects
0301 basic medicine ,Male ,Cancer Research ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Dasatinib ,urologic and male genital diseases ,Transcriptome ,Mice ,0302 clinical medicine ,Cell Movement ,U87 ,Brain Neoplasms ,Middle Aged ,Prognosis ,female genital diseases and pregnancy complications ,src-Family Kinases ,Oncology ,030220 oncology & carcinogenesis ,[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,embryonic structures ,Neoplastic Stem Cells ,Female ,Stem cell ,medicine.drug ,Adult ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,Biology ,Disease-Free Survival ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,CD90 ,Aged ,urogenital system ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cancer ,Gene signature ,medicine.disease ,Xenograft Model Antitumor Assays ,nervous system diseases ,030104 developmental biology ,Cancer cell ,Cancer research ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Thy-1 Antigens ,Glioblastoma - Abstract
Purpose: CD90 (Thy-1) is a glycophosphatidylinositol-anchored glycoprotein considered as a surrogate marker for a variety of stem cells, including glioblastoma (GBM) stem cells (GSC). However, the molecular and cellular functions of CD90 remain unclear. Experimental Design: The function of CD90 in GBM was addressed using cellular models from immortalized and primary GBM lines, in vivo orthotopic mouse models, and GBM specimens' transcriptome associated with MRI features from GBM patients. CD90 expression was silenced in U251 and GBM primary cells and complemented in CD90-negative U87 cells. Results: We showed that CD90 is not only expressed on GSCs but also on more differentiated GBM cancer cells. In GBM patients, CD90 expression was associated with an adhesion/migration gene signature and with invasive tumor features. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration properties. Moreover, orthotopic xenografts revealed that CD90 expression induced invasive phenotypes in vivo. Indeed, CD90 expression led to enhanced SRC and FAK signaling in our GBM cellular models and GBM patients' specimens. Pharmacologic inhibition of these signaling nodes blunted adhesion and migration in CD90-positive cells. Remarkably, dasatinib blunted CD90-dependent GBM cell invasion in vivo and killed CD90high primary GSC lines. Conclusions: Our data demonstrate that CD90 is an actor of GBM invasiveness through SRC-dependent mechanisms and could be used as a predictive factor for dasatinib response in CD90high GBM patients. Clin Cancer Res; 23(23); 7360–74. ©2017 AACR.
- Published
- 2017
42. Control of the Unfolded Protein Response in Health and Disease
- Author
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Dimitrios Doultsinos, Stéphanie Lhomond, Philippe Guedat, Eric Chevet, Nicolas Dejeans, Tony Avril, Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut Bergonié [Bordeaux], UNICANCER, Institut National du Cancer (INCa), EU [MSCA ITN-675448], and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
0301 basic medicine ,endocrine system ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Disease ,Bioinformatics ,digestive system ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,stress ,0302 clinical medicine ,Medicine ,Animals ,Humans ,[CHIM]Chemical Sciences ,Screening tool ,Physiological function ,business.industry ,Endoplasmic reticulum ,Clinical study design ,screening ,fungi ,upr ,Endoplasmic Reticulum Stress ,3. Good health ,endoplasmic reticulum ,030104 developmental biology ,Drug development ,030220 oncology & carcinogenesis ,biological sciences ,Immunology ,Unfolded protein response ,Unfolded Protein Response ,Molecular Medicine ,pharmacology ,business ,Biotechnology - Abstract
International audience; The unfolded protein response (UPR) is an integrated, adaptive biochemical process that is inextricably linked with cell homeostasis and paramount to maintenance of normal physiological function. Prolonged accumulation of improperly folded proteins in the endoplasmic reticulum (ER) leads to stress. This is the driving stimulus behind the UPR. As such, prolonged ER stress can push the UPR past beneficial functions such as reduced protein production and increased folding and clearance to apoptotic signaling. The UPR is thus contributory to the commencement, maintenance, and exacerbation of a multitude of disease states, making it an attractive global target to tackle conditions sorely in need of novel therapeutic intervention. The accumulation of information of screening tools, readily available therapies, and potential pathways to drug development is the cornerstone of informed clinical research and clinical trial design. Here, we review the UPR's involvement in health and disease and, beyond providing an in-depth description of the molecules found to target the three UPR arms, we compile all the tools available to screen for and develop novel therapeutic agents that modulate the UPR with the scope of future disease intervention.
- Published
- 2017
43. Reprint of: Signaling the Unfolded Protein Response in primary brain cancers
- Author
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Eric Chevet, Véronique Quillien, Pierre-Jean Le Reste, Tony Avril, Xavier Morandi, Service de neurochirurgie [Rennes] = Neurosurgery [Rennes], CHU Pontchaillou [Rennes], Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut National du Cancer (INCa), La Ligue Contre le Cancer, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)
- Subjects
0301 basic medicine ,endoplasmic-reticulum stress ,glucose-regulated protein ,medicine.medical_treatment ,hepatocellular-carcinoma ,Population ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Brain cancer ,03 medical and health sciences ,glioblastoma-multiforme cells ,Glioma ,choroid-plexus carcinoma ,Medicine ,education ,Molecular Biology ,breast-cancer ,transcription factor ,Potential impact ,Chemotherapy ,education.field_of_study ,business.industry ,General Neuroscience ,Endoplasmic reticulum ,malignant glioma ,medicine.disease ,mesenchymal transition ,er-stress ,3. Good health ,030104 developmental biology ,Immunology ,Cancer cell ,Unfolded protein response ,Cancer research ,Neurology (clinical) ,business ,Developmental Biology - Abstract
International audience; The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target. This article is part of a Special Issue entitled SI:ER stress. (C) 2016 Elsevier B.V. All rights reserved.
- Published
- 2016
44. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties
- Author
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Tony Avril, Delphine Fessart, Raphael Pineau, Hugues Begueret, Eric Chevet, Carlo Lucchesi, Camille Malrieux, Charlotte Domblides, Leif A. Eriksson, Frédéric Delom, Nathalie Dugot-Senant, Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogenesis Stress Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université de Bordeaux (UB), CRLCC Eugène Marquis (CRLCC), Dept Chem & Mol Biol, University of Gothenburg (GU), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Pathologies infectieuses et cancers : aspects biologiques et thérapeutiques (PICABT), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ligue Contre le Cancer, Institut National Du Cancer [INCa₅869], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,cell-proliferation ,Mouse ,Carcinogenesis ,Regulator ,migration ,localization ,Extracellular matrix ,Mucoproteins ,Neoplasms ,pancreatic-cancer ,Biology (General) ,anterior gradient-2 ,Cells, Cultured ,organoids ,Cancer Biology ,Epithelial polarity ,Oncogene Proteins ,General Neuroscience ,General Medicine ,Extracellular Matrix ,3. Good health ,endoplasmic reticulum ,Biochemistry ,Medicine ,Research Article ,AGR2 ,Human ,QH301-705.5 ,Science ,Morphogenesis ,epithelial-mesenchymal transition ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,survival ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,protein disulphide isomerase ,Extracellular ,Humans ,cancer ,metastasis ,Secretion ,extracellular-matrix ,General Immunology and Microbiology ,Endoplasmic reticulum ,Proteins ,Epithelial Cells ,tissue ,Cell Biology ,030104 developmental biology - Abstract
The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.13887.001, eLife digest Cancer cells multiply abnormally fast and therefore produce protein molecules faster than normal cells. To avoid becoming stressed by this overproduction, cancer cells make use of proteins that fold the new proteins inside the cell. One of these protein folders is called anterior gradient-2 (or AGR2 for short) and is produced at high levels in so-called epithelial cancers, such as breast and lung cancer. Previous research has shown that AGR2 inside cancer cells can help them grow and survive and AGR2 can also be found outside cells, such as in the blood or the urine of cancer patients. Therefore some researchers have suggested that measuring the levels of AGR2 in bodily fluids may be a useful marker for detecting cancers. Fessart et al. hypothesized that – apart from becoming a promising diagnostic tool – the AGR2 protein itself, specifically when found outside cells, might make cancer cells more aggressive. Fessart et al. used a range of techniques to test this hypothesis. For example, healthy lung cells and lung cancer cells were grown into miniature replicas of lung organs in the laboratory, and in a key experiment, AGR2 was added to the lung organoids grown from the healthy cells. The addition of AGR2 protein was enough to change the non-tumor organoids into tumor organoids and boosted their growth about ten-fold. Further experiments then revealed that AGR2 also makes cells more invasive and capable of moving, both important features of aggressive cancer cells. Overall, Fessart et al. have proven that AGR2 is a signalling molecule found outside cancer cells that makes them more aggressive. In future, more research addressing how AGR2 achieves this may lead to new therapeutic strategies against some forms of cancer. DOI: http://dx.doi.org/10.7554/eLife.13887.002
- Published
- 2016
45. Endoplasmic Reticulum Stress and the Hallmarks of Cancer
- Author
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Estefanie Dufey, Hery Urra, Eric Chevet, Claudio Hetz, Tony Avril, Universidad de Santiago de Chile [Santiago] (USACH), Biomedical Neuroscience Institute, Institute of Biomedical Sciences, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Department of Immunology and Infectious Diseases, Harvard School of Public Health, This work was funded by FONDECYT 24441789 (HU), Ecos-ConicytC13S02 (CH and EC), FONDECYT no. 1140549 (CH) and Institut National du Cancer (INCa), La Ligue Contre le Cancer (EC). We also thank Millennium Institute No. P09-015-F, and FONDAP 15150012, the Frick Foundation, ALS Therapy Alliance 2014-F-059, Muscular Dystrophy Association 382453, CONICYT-USA2013-0003, Michael J Fox Foundation for Parkinson´s Research, COPEC-UC Foundation, Office of Naval Research-Global (ONR-G) N62909-16-1-2003 and CDMRP Amyotrophic Lateral Sclerosis Research Program (ALSRP) Therapeutic Idea Award AL150111 (C.H.). ED is supported funded by a CONICYT fellowship., and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)
- Subjects
0301 basic medicine ,Genome instability ,Cancer Research ,Angiogenesis ,[SDV]Life Sciences [q-bio] ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,UPR ,Biology ,Genomic Instability ,Epigenesis, Genetic ,Metastasis ,03 medical and health sciences ,Neoplasms ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Cancer ,ATF6 ,Endoplasmic reticulum ,IRE1α ,Endoplasmic Reticulum Stress ,medicine.disease ,3. Good health ,Cell biology ,XBP1 ,Cell Transformation, Neoplastic ,030104 developmental biology ,Proteostasis ,Oncology ,Drug Resistance, Neoplasm ,Unfolded Protein Response ,Unfolded protein response ,ER stress - Abstract
International audience; Tumor cells are often exposed to intrinsic and external factors that alter protein homeostasis, thus producing endoplasmic reticulum (ER) stress. To cope with this, cells evoke an adaptive mechanism to restore ER proteostasis known as the unfolded protein response (UPR). The three main UPR signaling branches initiated by IRE1α, PERK, and ATF6 are crucial for tumor growth and aggressiveness as well as for microenvironment remodeling or resistance to treatment. We provide a comprehensive overview of the contribution of the UPR to cancer biology and the acquisition of malignant characteristics, thus highlighting novel aspects including inflammation, invasion and metastasis, genome instability, resistance to chemo/radiotherapy, and angiogenesis. The therapeutic potential of targeting ER stress signaling in cancer is also discussed.
- Published
- 2016
46. Author response: Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties
- Author
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Raphael Pineau, Charlotte Domblides, Tony Avril, Camille Malrieux, Delphine Fessart, Carlo Lucchesi, Leif A. Eriksson, Hugues Begueret, Frédéric Delom, Eric Chevet, and Nathalie Dugot-Senant
- Subjects
Biochemistry ,Chemistry ,AGR2 ,Secretion ,Protein disulphide-isomerase - Published
- 2016
47. Signaling the Unfolded Protein Response in primary brain cancers
- Author
-
Véronique Quillien, Tony Avril, Pierre-Jean Le Reste, Xavier Morandi, Eric Chevet, CHU Pontchaillou [Rennes], Oncogenesis Stress Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), We apologize to colleagues whose work was not cited in this article due to space limitation. This work was supported by grants from Institut National du Cancer (INCa) and La Ligue Contre le Cancer to EC., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
- Subjects
0301 basic medicine ,Choroid Plexus Neoplasms ,medicine.medical_treatment ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Population ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,UPR ,Stress ,Pineal Gland ,Brain cancer ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Glioma ,Meningeal Neoplasms ,Medicine ,Animals ,Humans ,education ,Cerebellar Neoplasms ,Molecular Biology ,brain cancer ,Chemotherapy ,education.field_of_study ,business.industry ,Brain Neoplasms ,General Neuroscience ,Endoplasmic reticulum ,Limiting nutrient ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.disease ,Endoplasmic Reticulum Stress ,3. Good health ,030104 developmental biology ,Immunology ,Cancer cell ,Cancer research ,Unfolded protein response ,Unfolded Protein Response ,Neurology (clinical) ,business ,Glioblastoma ,Meningioma ,Pinealoma ,Developmental Biology ,Medulloblastoma ,Signal Transduction - Abstract
International audience; The Unfolded Protein Response (UPR) is an adaptive cellular program used by eukaryotic cells to cope with protein misfolding stress in the Endoplasmic Reticulum (ER). During tumor development, cancer cells are facing intrinsic (oncogene activation) and extrinsic (limiting nutrient or oxygen supply; exposure to chemotherapies) challenges, with which they must cope to survive. Primary brain tumors are relatively rare but deadly and present a significant challenge in the determination of risk factors in the population. These tumors are inherently difficult to cure because of their protected location in the brain. As such surgery, radiation and chemotherapy options carry potentially lasting patient morbidity and incomplete tumor cure. Some of these tumors, such as glioblastoma, were reported to present features of ER stress and to depend on UPR activation to sustain growth, but to date there is no clear general representation of the ER stress status in primary brain tumors. In this review, we describe the key molecular mechanisms controlling the UPR and their implication in cancers. Then we extensively review the literature reporting the status of ER stress in various primary brain tumors and discuss the potential impact of such observation on patient stratification and on the possibility of developing appropriate targeted therapies using the UPR as therapeutic target
- Published
- 2016
48. Proteostasis trumps YAP in colon cancer
- Author
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Eric Chevet, Tony Avril, Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), CRLCC Eugène Marquis (CRLCC), Institut National Du Cancer, Ligue Contre le Cancer, and Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)
- Subjects
Colorectal cancer ,[SDV]Life Sciences [q-bio] ,Cell Biology ,Biology ,Bioinformatics ,medicine.disease ,Biochemistry ,Verteporfin ,3. Good health ,Proteostasis ,Proteotoxicity ,Cancer cell ,medicine ,Cancer research ,Molecular Biology ,medicine.drug - Abstract
International audience; In this issue of Science Signaling, Zhang et al. find a new role for verteporfin in the control of colorectal cancer progression through the selective induction of proteotoxicity rather than through inhibition of the transcription cofactor YAP. The study further documents the potential strategy of targeting proteostasis to kill cancer cells
- Published
- 2015
49. Human Glioblastoma Stem-Like Cells are More Sensitive to Allogeneic NK and T Cell-Mediated Killing Compared with Serum-Cultured Glioblastoma Cells
- Author
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Abderrahmane Hamlat, Stephan Saikali, Amandine Etcheverry, Caroline Delmas, Sylma Diabira, Véronique Quillien, Elodie Vauleon, Tony Avril, and Jean Mosser
- Subjects
endocrine system ,0303 health sciences ,General Neuroscience ,T cell ,medicine.medical_treatment ,fungi ,Immunotherapy ,Biology ,3. Good health ,Pathology and Forensic Medicine ,Cell therapy ,03 medical and health sciences ,Interleukin 21 ,0302 clinical medicine ,Immune system ,medicine.anatomical_structure ,Cancer stem cell ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,medicine ,Cytotoxic T cell ,Neurology (clinical) ,Stem cell ,030304 developmental biology - Abstract
Glioblastoma multiforme (GBM) is the most dramatic primary brain cancer with a very poor prognosis because of inevitable disease recurrence. The median overall survival is less than 1 year after diagnosis. Cancer stem cells have recently been disclosed in GBM. GBM stem-like cells (GSCs) exhibit resistance to radio/chemotherapeutic treatments and are therefore considered to play an important role in disease recurrence. GSCs are thus appealing targets for new treatments for GBM patients. In this study, we show that GBM cells with stem cell characteristics are resistant to lysis mediated by resting natural killer (NK) cells because of the expression of MHC class I molecules. However, GSCs are killed by lectin-activated NK cells. Furthermore, in experiments using the therapeutic antibody CetuximAb, we show that GSCs are sensitive to antibody-mediated cytotoxicity. We confirm the sensitivity of GSC to cytotoxicity carried out by IL2-activated NK cells and tumor-specific T cells. More importantly, we show that GSCs are more sensitive to NK and T cell-mediated lysis relatively to their corresponding serum-cultured GBM cells obtained from the same initial tumor specimen. Altogether, these results demonstrate the sensitivity of GSC to immune cell cytotoxicity and, therefore, strongly suggest that GSCs are suitable target cells for immunotherapy of GBM patients.
- Published
- 2011
50. Safety, Pharmacokinetic, and Pharmacodynamic Evaluations of PI-2301, a Potent Immunomodulator, in a First-in-Human, Single-Ascending-Dose Study in Healthy Volunteers
- Author
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Edward Mascioli, Nicolas Fauchoux, Jeffrey Krieger, Michelle Genova, E. Lacoste, Joseph Kovalchin, Michael Augustyniak, Kathy Collins, Tony Avril, Claire Toutin, Uday Patel, Eric Zanelli, Alain Patat, Gwenola Gandon, and Allyson Masci
- Subjects
Adult ,Male ,Adolescent ,Side effect ,Polymers ,Injections, Subcutaneous ,T-Lymphocytes ,Pharmacology ,Lymphocyte Activation ,Chemokine CXCL9 ,Antibodies ,Interferon-gamma ,Young Adult ,Subcutaneous injection ,Immune system ,Double-Blind Method ,Pharmacokinetics ,Humans ,Immunologic Factors ,Medicine ,Pharmacology (medical) ,Dosing ,Cells, Cultured ,Aged ,Cell Proliferation ,Interleukin-13 ,Dose-Response Relationship, Drug ,business.industry ,Proteins ,Middle Aged ,Chemokine CXCL10 ,Pharmacodynamics ,CXCL9 ,France ,business ,Oligopeptides ,Biomarkers ,Ex vivo - Abstract
PI-2301 is an amino acid copolymer acting as an immunomodulator for the treatment of autoimmune diseases. The present study evaluated the safety, pharmacokinetics (PK), and pharmacodynamics of PI-2301 in a single ascending dose, first-in-human study involving healthy, male adult volunteers. A total of 56 subjects were given a subcutaneous injection of PI-2301 ranging from 0.035 to 60 mg. The only consistent side effect was transient injection site reactions. We describe, for the first time, a pharmacokinetic assay to monitor amino acid copolymer concentration in human serum. PI-2301 was detected in the serum of subjects in the 10-, 30-, and 60-mg cohorts. Maximum serum concentration was achieved between 10 and 30 minutes postdosing with some compound detected 4 hours after dosing. PI-2301's lasting immunological properties were evident by an ex vivo recall assay showing T-cell proliferation and IL-13 production in subjects dosed with 1, 3, or 10 mg of PI-2301, up to 6 months after dosing. A transient increase in chemokine CXCL9 and CXCL10 plasma levels was seen in subjects dosed with 30 or 60 mg of PI-2301. These results are highly consistent with our preclinical findings and suggest that PI-2301 could facilitate the expansion of a favorable immune posture in patients with autoimmune disorders.
- Published
- 2011
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