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1. Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma via aberrant expression of KCNN1/SK1 and dysregulation of calcium signaling

Author

Dupuy, Maryne, Gueguinou, Maxime, Postec, Anaïs, Brion, Régis, Tesfaye, Robel, Mullard, Mathilde, Regnier, Laura, Amiaud, Jérôme, Hubsch, Clémence, Potier-Cartereau, Marie, Chantôme, Aurélie, Brounais-Le Royer, Bénédicte, Baud’huin, Marc, Georges, Steven, Lamoureux, François, Ory, Benjamin, Entz-Werlé, Natacha, Delattre, Olivier, Rédini, Françoise, Vandier, Christophe, and Verrecchia, Franck

Published
2024
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2. Tracking Targets of Dynamic Super-Enhancers in Vitro to Better Characterize Osteoclastogenesis and to Evaluate the Effect of Diuron on the Maturation of Human Bone Cells

Author

Tesfaye, Robel A., Lavaud, Melanie, Charrier, Celine, Brounais-Le Royer, Benedicte, Cartron, Pierre-Francois, Verrecchia, Franck, Baud'huin, Marc, Lamoureux, Francois, Georges, Steven, and Ory, Benjamin

Subjects
Herbicides -- Environmental aspects -- Health aspects -- Genetic aspects, Osteoblasts -- Physiological aspects -- Health aspects, Osteoclasts (Biology) -- Physiological aspects -- Health aspects, Cell differentiation -- Genetic aspects -- Health aspects, Environmental issues, Health
Abstract

Background: Osteoclasts are major actors in the maintenance of bone homeostasis. The full functional maturation of osteoclasts from monocyte lineage cells is essential for the degradation of old/damaged bone matrix. Diuron is one of the most frequently encountered herbicides, particularly in water sources. However, despite a reported delayed ossification in vivo, its impact on bone cells remains largely unknown. Objectives: The objectives of this study were to first better characterize osteoclastogenesis by identifying genes that drive the differentiation of [CD14.sup.+] monocyte progenitors into osteoclasts and to evaluate the toxicity of diuron on osteoblastic and osteoclastic differentiation in vitro. Methods: We performed chromatin immunoprecipitation (ChIP) against H3K27ac followed by ChIP-sequencing (ChIP-Seq) and RNA-sequencing (RNA-Seq) at different stages of differentiation of [CD14.sup.+] monocytes into active osteoclasts. Differentially activated super-enhancers and their potential target genes were identified. Then to evaluate the toxicity of diuron on osteoblasts and osteoclasts, we performed RNA-Seq and functional tests during in vitro osteoblastic and osteoclastic differentiation by exposing cells to different concentrations of diuron. RESULTS: The combinatorial study of the epigenetic and transcriptional remodeling taking place during differentiation has revealed a very dynamic epigenetic profile that supports the expression of genes vital for osteoclast differentiation and function. In total, we identified 122 genes induced by dynamic super-enhancers at late days. Our data suggest that high concentration of diuron (50 [micro]M) affects viability of mesenchymal stem cells (MSCs) in vitro associated with a decrease of bone mineralization. At a lower concentration (1 [micro]M), an inhibitory effect was observed in vitro on the number of osteoclasts derived from [CD14.sup.+] monocytes without affecting cell viability. Among the diuron-affected genes, our analysis suggests a significant enrichment of genes targeted by pro-differentiation super-enhancers, with an odds ratio of 5.12 (p = 2.59 * [10.sup.-5]). DISCUSSION: Exposure to high concentrations of diuron decreased the viability of MSCs and could therefore affect osteoblastic differentiation and bone mineralization. This pesticide also disrupted osteoclasts maturation by impairing the expression of cell-identity determining genes. Indeed, at sublethal concentrations, differences in the expression of these key genes were mild during the course of in vitro osteoclast differentiation. Taken together our results suggest that high exposure levels of diuron could have an effect on bone homeostasis. https://doi.org/10.1289/EHP11690, Introduction Bone tissue is maintained through continual bone remodeling during the life of an individual. This process involves mainly two cell types: the osteoblasts and the osteoclasts, respectively producing and [...]

Published
2023
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4. Ewing sarcoma from molecular biology to the clinic

Author

Dupuy, Maryne, primary, Lamoureux, François, additional, Mullard, Mathilde, additional, Postec, Anaïs, additional, Regnier, Laura, additional, Baud’huin, Marc, additional, Georges, Steven, additional, Brounais-Le Royer, Bénédicte, additional, Ory, Benjamin, additional, Rédini, Françoise, additional, and Verrecchia, Franck, additional

Published
2023
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5. Exploration of the ocular surface infection by SARS-CoV-2 and implications for corneal donation: An ex vivo study

Author

Maurin, Corantin, He, Zhiguo, Mentek, Marielle, Verhoeven, Paul, Pillet, Sylvie, Bourlet, Thomas, Rogues, Françoise, Pugniet, Jean Loup, Peyragrosse, Thierry, Barallon, Marion, Perrache, Chantal, Aouimeur, Inès, Acquart, Sophie, Ninotta, Sandrine, Baud'huin, Marc, Vabres, Bertrand, Poinard, Sylvain, Gain, Philippe, and Thuret, Gilles

Subjects
Eye infections -- Risk factors, Medical research, Medicine, Experimental, Cornea -- Transplantation, Disease transmission -- Methods, Donation of organs, tissues, etc. -- Management, Company business management, Company distribution practices, Biological sciences
Abstract

Background The risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmission through corneal graft is an ongoing debate and leads to strict restrictions in corneas procurement, leading to a major decrease in eye banking activity. The aims of this study are to specifically assess the capacity of human cornea to be infected by SARS-CoV-2 and promote its replication ex vivo, and to evaluate the real-life risk of corneal contamination by detecting SARS-CoV-2 RNA in corneas retrieved in donors diagnosed with Coronavirus Disease 2019 (COVID-19) and nonaffected donors. Methods and findings To assess the capacity of human cornea to be infected by SARS-CoV-2, the expression pattern of SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE-2) and activators TMPRSS2 and Cathepsins B and L in ocular surface tissues from nonaffected donors was explored by immunohistochemistry (n = 10 corneas, 78 ± 11 years, 40% female) and qPCR (n = 5 corneas, 80 ± 12 years, 40% female). Additionally, 5 freshly excised corneas (80 ± 12 years, 40% female) were infected ex vivo with highly concentrated SARS-CoV-2 solution (10.sup.6 median tissue culture infectious dose (TCID.sub.50 )/mL). Viral RNA was extracted from tissues and culture media and quantified by reverse transcription quantitative PCR (RT-qPCR) (viral RNA copies) 30 minutes (H0) and 24 hours (H24) after infection. To assess the risk of corneal contamination by SARS-CoV-2, viral RNA was tested by RT-qPCR (Ct value) in both corneas and organ culture media from 14 donors diagnosed with COVID-19 (74 ± 10 years, 29% female) and 26 healthy donors (79 ± 13 years, 57% female), and in organ culture media only from 133 consecutive nonaffected donors from 2 eye banks (73 ± 13 years, 29% female). The expression of receptor and activators was variable among samples at both protein and mRNA level. Based on immunohistochemistry findings, ACE-2 was localized mainly in the most superficial epithelial cells of peripheral cornea, limbus, and conjunctiva, whereas TMPRSS2 was mostly expressed in all layers of bulbar conjunctiva. A significant increase in total and positive strands of IP4 RNA sequence (RdRp viral gene) was observed from 30 minutes to 24 hours postinfection in central cornea (1.1 x 10.sup.8 [95% CI: 6.4 x 10.sup.7 to 2.4 x 10.sup.8 ] to 3.0 x 10.sup.9 [1.4 x 10.sup.9 to 5.3 x 10.sup.9 ], p = 0.0039 and 2.2 x 10.sup.7 [1.4 x 10.sup.7 to 3.6 x 10.sup.7 ] to 5.1 x 10.sup.7 [2.9 x 10.sup.7 to 7.5 x 10.sup.7 ], p = 0.0117, respectively) and in corneoscleral rim (4.5 x 10.sup.9 [2.7 x 10.sup.9 to 9.6 x 10.sup.9 ] to 3.9 x 10.sup.10 [2.6 x 10.sup.10 to 4.4 x 10.sup.10 ], p = 0.0039 and 3.1 x 10.sup.8 [1.2 x 10.sup.8 to 5.3 x 10.sup.8 ] to 7.8 x 10.sup.8 [3.9 x 10.sup.8 to 9.9 x 10.sup.8 ], p = 0.0391, respectively). Viral RNA copies in ex vivo corneas were highly variable from one donor to another. Finally, viral RNA was detected in 3 out of 28 corneas (11%) from donors diagnosed with COVID-19. All samples from the 159 nonaffected donors were negative for SARS-CoV-2 RNA. The main limitation of this study relates to the limited sample size, due to limited access to donors diagnosed with COVID-19 and concomitant decrease in the procurement corneas from nonaffected donors. Conclusions In this study, we observed the expression of SARS-CoV-2 receptors and activators at the human ocular surface and a variable increase in viral RNA copies 24 hours after experimental infection of freshly excised human corneas. We also found viral RNA only in a very limited percentage of donors with positive nasopharyngeal PCR. The low rate of positivity in donors diagnosed with COVID-19 calls into question the utility of donor selection algorithms. Trial registration Agence de la Biomédecine, PFS-20-011 https://www.agence-biomedecine.fr/., Author(s): Corantin Maurin 1, Zhiguo He 1, Marielle Mentek 1, Paul Verhoeven 2,3, Sylvie Pillet 2,3, Thomas Bourlet 2,3, Françoise Rogues 4, Jean Loup Pugniet 4, Thierry Peyragrosse 4, Marion [...]

Published
2022
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7. Supplementary Table S1 and S2 from Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, primary, Verrecchia, Franck, primary, Royer, Bénédicte Brounais-Le, primary, Quillard, Thibaut, primary, Amiaud, Jérôme, primary, Battaglia, Séverine, primary, Heymann, Dominique, primary, Redini, Francoise, primary, and Lamoureux, Francois, primary

Published
2023
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8. Supplemental Figure 3 from Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, primary, Verrecchia, Franck, primary, Royer, Bénédicte Brounais-Le, primary, Quillard, Thibaut, primary, Amiaud, Jérôme, primary, Battaglia, Séverine, primary, Heymann, Dominique, primary, Redini, Francoise, primary, and Lamoureux, Francois, primary

Published
2023
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9. Supplemental Figure 2 from Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, primary, Verrecchia, Franck, primary, Royer, Bénédicte Brounais-Le, primary, Quillard, Thibaut, primary, Amiaud, Jérôme, primary, Battaglia, Séverine, primary, Heymann, Dominique, primary, Redini, Francoise, primary, and Lamoureux, Francois, primary

Published
2023
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10. supplemental figure legend from Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, primary, Verrecchia, Franck, primary, Royer, Bénédicte Brounais-Le, primary, Quillard, Thibaut, primary, Amiaud, Jérôme, primary, Battaglia, Séverine, primary, Heymann, Dominique, primary, Redini, Francoise, primary, and Lamoureux, Francois, primary

Published
2023
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11. Supplemental Figure 1 from Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, primary, Verrecchia, Franck, primary, Royer, Bénédicte Brounais-Le, primary, Quillard, Thibaut, primary, Amiaud, Jérôme, primary, Battaglia, Séverine, primary, Heymann, Dominique, primary, Redini, Francoise, primary, and Lamoureux, Francois, primary

Published
2023
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12. Supplementary Figure S2 from ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Rodriguez Calleja, Lidia, primary, Jacques, Camille, primary, Lamoureux, François, primary, Baud'huin, Marc, primary, Tellez Gabriel, Marta, primary, Quillard, Thibaut, primary, Sahay, Debashish, primary, Perrot, Pierre, primary, Amiaud, Jerome, primary, Charrier, Celine, primary, Brion, Regis, primary, Lecanda, Fernando, primary, Verrecchia, Franck, primary, Heymann, Dominique, primary, Ellisen, Leif W., primary, and Ory, Benjamin, primary

Published
2023
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13. Data from ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Rodriguez Calleja, Lidia, primary, Jacques, Camille, primary, Lamoureux, François, primary, Baud'huin, Marc, primary, Tellez Gabriel, Marta, primary, Quillard, Thibaut, primary, Sahay, Debashish, primary, Perrot, Pierre, primary, Amiaud, Jerome, primary, Charrier, Celine, primary, Brion, Regis, primary, Lecanda, Fernando, primary, Verrecchia, Franck, primary, Heymann, Dominique, primary, Ellisen, Leif W., primary, and Ory, Benjamin, primary

Published
2023
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14. Supplementary Figure Legends from ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Rodriguez Calleja, Lidia, primary, Jacques, Camille, primary, Lamoureux, François, primary, Baud'huin, Marc, primary, Tellez Gabriel, Marta, primary, Quillard, Thibaut, primary, Sahay, Debashish, primary, Perrot, Pierre, primary, Amiaud, Jerome, primary, Charrier, Celine, primary, Brion, Regis, primary, Lecanda, Fernando, primary, Verrecchia, Franck, primary, Heymann, Dominique, primary, Ellisen, Leif W., primary, and Ory, Benjamin, primary

Published
2023
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15. Chimeric protein EWS::FLI1 drives cell proliferation in Ewing Sarcoma viaaberrant expression of KCNN1/SK1 and dysregulation of calcium signaling

Author

Dupuy, Maryne, Gueguinou, Maxime, Postec, Anaïs, Brion, Régis, Tesfaye, Robel, Mullard, Mathilde, Regnier, Laura, Amiaud, Jérôme, Hubsch, Clémence, Potier-Cartereau, Marie, Chantôme, Aurélie, Brounais-Le Royer, Bénédicte, Baud’huin, Marc, Georges, Steven, Lamoureux, François, Ory, Benjamin, Entz-Werlé, Natacha, Delattre, Olivier, Rédini, Françoise, Vandier, Christophe, and Verrecchia, Franck

Abstract

Ewing sarcoma (ES) is characterized by EWS::FLI1 or EWS::ERG fusion proteins. Knowing that ion channels are involved in tumorigenesis, this work aimed to study the involvement of the KCNN1gene, which encodes the SK1 potassium channel, in ES development. Bioinformatics analyses from databases were used to study KCNN1expression in patients and cell lines. Molecular approaches and in vitro assays were used to study the transcriptional regulation of KCNN1and its involvement in the regulation of ES cell proliferation. KCNN1is overexpressed in ES patient biopsies, and its expression is inversely correlated with patient survival. EWS::FLI1, like EWS::ERG, promotes KCNN1and SK1 expression, binding to GGAA microsatellites near the promoter of KCNN1isoforms. KCNN1is involved in the regulation of ES cell proliferation, with its silencing being associated with a slowing of the cell cycle, and its expression modulates membrane potential and therefore calcium flux. These results highlight that KCNN1is a direct target of EWS::FLI1 and EWS::ERG and demonstrate that KCNN1is involved in the regulation of intracellular calcium activity and ES cell proliferation, making it a promising therapeutic target in ES.

Published
2024
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17. Origin and Therapies of Osteosarcoma

Author

Moukengue, Brice, primary, Lallier, Morgane, additional, Marchandet, Louise, additional, Baud’huin, Marc, additional, Verrecchia, Franck, additional, Ory, Benjamin, additional, and Lamoureux, Francois, additional

Published
2022
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18. Abstract 3902: TRIM33 interacts with HSF1 in osteosarcoma development

Author

Lallier, Morgane, primary, Tefaye, Robel, additional, Moukengué, Brice, additional, Charrier, Céline, additional, Thepault, Rose-Anne, additional, Royer, Benedicte Brounais-Le, additional, Baud'huin, Marc, additional, Verrecchia, Franck, additional, Ory, Benjamin, additional, and Lamoureux, François, additional

Published
2022
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20. Abstract 6325: Identification of genes responsible for osteosarcomas metastatic evolution by active super enhancers profiling

Author

Lavaud, Mélanie, primary, Tesfaye, Robel, additional, Charrier, Céline, additional, Thépault, Rose Anne, additional, Golias, Maxime, additional, Page, Sarah Le, additional, Mullard, Mathilde, additional, Brounais, Bénédicte, additional, Verrecchia, Franck, additional, Baud'huin, Marc, additional, Lamoureux, François, additional, Georges, Steven, additional, and Ory, Benjamin, additional

Published
2022
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22. One threat, different answers: the impact of COVID-19 pandemic on cornea donation and donor selection across Europe

Author

Thuret, Gilles, Courrier, Emilie, Poinard, Sylvain, Gain, Philippe, Baud'Huin, Marc, Martinache, Isabelle, Cursiefen, Claus, Maier, Philip, Hjortdal, Jesper, Ibanez, Jacinto Sanchez, Ponzin, Diego, Ferrari, Stefano, Jones, Gary, Griffoni, Carlo, Rooney, Paul, Bennett, Kyle, Armitage, W. John, Figueiredo, Francisco, Nuijts, Rudy, Dickman, Mor, Thuret, Gilles, Courrier, Emilie, Poinard, Sylvain, Gain, Philippe, Baud'Huin, Marc, Martinache, Isabelle, Cursiefen, Claus, Maier, Philip, Hjortdal, Jesper, Ibanez, Jacinto Sanchez, Ponzin, Diego, Ferrari, Stefano, Jones, Gary, Griffoni, Carlo, Rooney, Paul, Bennett, Kyle, Armitage, W. John, Figueiredo, Francisco, Nuijts, Rudy, and Dickman, Mor

Abstract

Objectives To assess to which extent the COVID-19 pandemic affected corneal transplantation by virtue of donor selection algorithms in different European countries. Design Survey. Setting 110 eye banks in 26 European countries. Participants 64 eye banks covering 95% of European corneal transplantation activity. Interventions A questionnaire listing the number of corneas procured and distributed from February to May 2018-2020 was circulated to eye banks. Main outcome measures The primary outcome was the number of corneal procurements. Additional outcomes were national algorithms for donor selection, classified according to their stringency (donors with COVID-19 history, suspected for COVID-19, asymptomatic, PCR testing) and the pandemic severity in each country. We calculated Spearman's correlation coefficient to determine, two by two, the relationship between the 3-month decline in eye banking activity (procurement), the stringency of donor selection algorithm and the grading of pandemic severity (cases and deaths). A partial correlation was run to determine the relationship between decline and stringency while controlling for pandemic severity. Results Procurements decreased by 38%, 68% and 41%, respectively, in March, April and May 2020 compared with the mean of the previous 2 years, while grafts decreased, respectively, by 28%, 68% and 56% corresponding to 3866 untreated patients in 3 months. Significant disparities between countries and the decrease in activity correlated with stringency in donor selection independent of pandemic severity. Conclusions Our data demonstrate significant differences between countries regarding donor screening algorithms based on precautionary principles and, consequently, a decrease in the donor pool, already constrained by a long list of contraindications. Fundamental studies are needed to determine the risk of SARS-CoV-2 transmission by corneal transplantation and guide evidence-based recommendations for donor selection to justify

Published
2022

26. Ribosomopathies: New Therapeutic Perspectives

Author

Orgebin, Emilien, Lamoureux, François, Isidor, Bertrand, Charrier, Céline, Ory, Benjamin, Lézot, Frédéric, Baud’huin, Marc, BAUD'HUIN, Marc, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)

Subjects
Ribosomal Proteins, riboprotein, treatment, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Review, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, ribosome, Humans, lcsh:QH301-705.5, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Ribosomes, ComputingMilieux_MISCELLANEOUS, ribosomopathies, Anemia, Diamond-Blackfan
Abstract

Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond–Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.

Published
2020

27. Implication of the p53-Related miR-34c, -125b, and -203 in the Osteoblastic Differentiation and the Malignant Transformation of Bone Sarcomas

Author

Jacques, Camille, Tesfaye, Robel, Lavaud, Melanie, Georges, Steven, Baud'Huin, Marc, Lamoureux, François, Ory, Benjamin, Baud’huin, Marc, Equipe Labellisée LIGUE 2012 [Nantes], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
musculoskeletal diseases, Osteoblasts, [SDV]Life Sciences [q-bio], Bone Neoplasms, Cell Differentiation, Review, bone, microRNAs, Cell Transformation, Neoplastic, lcsh:Biology (General), osteosarcoma, Animals, Humans, Tumor Suppressor Protein p53, lcsh:QH301-705.5
Abstract

International audience; The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.

Published
2020

28. BET bromodomains' functions in bone-related pathologies

Author

Jacques, Camille, Lavaud, Melanie, Georges, Steven, Tesfaye, Robel, Baud'Huin, Marc, Lamoureux, François, Ory, Benjamin, Baud’huin, Marc, Equipe Labellisée LIGUE 2012 [Nantes], Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Cancer Research, BRD4, JQ1, [SDV]Life Sciences [q-bio], Osteoporosis, Context (language use), Bone Neoplasms, Sarcoma, Ewing, Biology, Bioinformatics, I-BET, bone, Epigenesis, Genetic, Histones, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Genetics, medicine, Humans, Epigenetics, 030304 developmental biology, BET bromodomains, 0303 health sciences, chondrosarcoma, Osteosarcoma, Mechanism (biology), Proteins, Acetylation, medicine.disease, Bromodomain, Primary bone, 030220 oncology & carcinogenesis, Protein Processing, Post-Translational, Ewing sarcoma, epigenetic
Abstract

International audience; Throughout life, bones are subjected to the so-called 'bone-remodeling' process, which is a balanced mechanism between the apposition and the resorption of bone. This remodeling process depends on the activities of bone-specialized cells, namely the osteoblasts and the osteoclasts. Any deregulation in this process results in bone-related pathologies, classified as either metabolic nonmalignant diseases (such as osteoporosis) or malignant primary bone sarcomas. As these pathologies are not characterized by common targetable genetic alterations, epigenetic strategies could be relevant and promising options. Recently, targeting epigenetic regulators such as the bromodomains and extraterminal domains (BET) readers have achieved success in numerous other pathologies, including cancers. In this review, we highlight the current state of the art in terms of the diverse implications of BET bromodomain proteins in the bone's biology and its defects. Consequently, their role in bone-related pathologies will also be developed, especially in the context of the primary bone sarcomas.

Published
2019

30. Molecular Chaperones in Osteosarcoma: Diagnosis and Therapeutic Issues

Author

Lallier, Morgane, Marchandet, Louise, Moukengue, Brice, Charrier, Celine, Baud’huin, Marc, Verrecchia, Franck, Ory, Benjamin, and Lamoureux, François

Subjects
endocrine system, Carcinogenesis, HSPs, Bone Neoplasms, Review, bone tumor, HSF1, Models, Biological, lcsh:Biology (General), osteosarcoma, Animals, Humans, lcsh:QH301-705.5, Heat-Shock Proteins, Molecular Chaperones
Abstract

Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying new therapeutic targets is thus essential. Heat Shock Proteins (HSPs) are the main effectors of Heat Shock Response (HSR), the expression of which is induced by stressors. HSPs are a large family of proteins involved in the folding and maturation of other proteins in order to maintain proteostasis. HSP overexpression is observed in many cancers, including breast, prostate, colorectal, lung, and ovarian, as well as OS. In this article we reviewed the significant role played by HSPs in molecular mechanisms leading to OS development and progression. HSPs are directly involved in OS cell proliferation, apoptosis inhibition, migration, and drug resistance. We focused on HSP27, HSP60, HSP70 and HSP90 and summarized their potential clinical uses in OS as either biomarkers for diagnosis or therapeutic targets. Finally, based on different types of cancer, we consider the advantage of targeting heat shock factor 1 (HSF1), the major transcriptional regulator of HSPs in OS.

Published
2021

32. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases 1 development in osteosarcoma model 2 3

Author

Moukengue, Brice, Brown, Hannah, Charrier, Eline, Battaglia, Everine, Baud'Huin, Marc, Quillard, Thibaut, Pham, Therese, Pateras, Ioannis, Gorgoulis, Vassilis, Helleday, Thomas, Heymann, Dominique, Warpman Berglund, Ulrika, Ory, Benjamin, Lamoureux, François, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Oncology and Metabolism [Sheffield, UK] (European Associated Laboratory 'Sarcoma Research Unit'), The University of Sheffield [Sheffield, U.K.], Department of Oncology and Metabolism [Sheffield, UK], Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm], National and Kapodistrian University of Athens (NKUA), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Oncology and Metabolism [Sheffield, UK] (INSERM European Associated Laboratory 'Sarcoma Research Unit'), and maurice, sandrine

Subjects
Osteosarcoma, [SDV.CAN] Life Sciences [q-bio]/Cancer, DNA damage, ROS, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone tumours, MTH1
Abstract

International audience; Background: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor res-ponders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. Methods: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. Findings: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover , 90 mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. Interpretation: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. Funding: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Sant e.

Published
2020

33. Molecular Alterations Associated with Osteosarcoma Development

Author

Kosei Ando, Kanji Mori, Franck Verrecchia, Baud’huin Marc, Françoise Rédini, and Dominique Heymann

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion, survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently, recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for osteosarcoma treatment to improve the clinical outcome.

Published
2012
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34. Proteoglycans: key partners in bone cell biology

Author

Lamoureux, Francois, Baud'huin, Marc, Heymann, Dominique, Redini, Francoise, and Duplomb, Laurence

Subjects
Proteoglycans -- Physiological aspects, Proteoglycans -- Health aspects, Bone resorption -- Research, Osteoma -- Research, Cytology -- Research, Biological sciences
Abstract

The complex proteoglycan (PG) composition in bone is addressed together with the specific role played by PGs in bone biology, as regulatory molecules for bone resorption and their involvement in bone tumor development. The roles of anl PG (HSPG) families as bone pro-resorptive agents and promoters of asteolytic tumor have made them good targets for new therapeutic approaches to these osteolytic bone tumors.

Published
2007

36. Proteoglycans and Osteolysis

Author

Baud’Huin, Marc, primary, Charrier, Céline, additional, Bougras, Gwenola, additional, Brion, Régis, additional, Lezot, Frédéric, additional, Padrines, Marc, additional, and Heymann, Dominique, additional

Published
2011
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38. One threat, different answers: the impact of COVID-19 pandemic on cornea donation and donor selection across Europe

Author

Thuret, Gilles, primary, Courrier, Emilie, additional, Poinard, Sylvain, additional, Gain, Philippe, additional, Baud'Huin, Marc, additional, Martinache, Isabelle, additional, Cursiefen, Claus, additional, Maier, Philip, additional, Hjortdal, Jesper, additional, Sanchez Ibanez, Jacinto, additional, Ponzin, Diego, additional, Ferrari, Stefano, additional, Jones, Gary, additional, Griffoni, Carlo, additional, Rooney, Paul, additional, Bennett, Kyle, additional, Armitage, W John, additional, Figueiredo, Francisco, additional, Nuijts, Rudy, additional, and Dickman, Mor, additional

Published
2020
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40. TH1579, MTH1 inhibitor, delays tumour growth and inhibits metastases development in osteosarcoma model

Author

Moukengue, Brice, primary, Brown, Hannah K, additional, Charrier, Céline, additional, Battaglia, Séverine, additional, Baud'huin, Marc, additional, Quillard, Thibaut, additional, Pham, Therese M, additional, Pateras, Ioannis S, additional, Gorgoulis, Vassilis G, additional, Helleday, Thomas, additional, Heymann, Dominique, additional, Berglund, Ulrika Warpman, additional, Ory, Benjamin, additional, and Lamoureux, Francois, additional

Published
2020
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42. RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature

Author

Le Caignec, Cedric, primary, Ory, Benjamin, additional, Lamoureux, François, additional, O’Donohue, Marie-Francoise, additional, Orgebin, Emilien, additional, Lindenbaum, Pierre, additional, Téletchéa, Stéphane, additional, Saby, Manon, additional, Hurst, Anna, additional, Nelson, Katherine, additional, Gilbert, Shawn R., additional, Wilnai, Yael, additional, Zeitlin, Leonid, additional, Segev, Eitan, additional, Tesfaye, Robel, additional, Nizon, Mathilde, additional, Cogne, Benjamin, additional, Bezieau, Stéphane, additional, Geoffroy, Loic, additional, Hamel, Antoine, additional, Mayrargue, Emmanuelle, additional, de Courtivron, Benoît, additional, Decock-Giraudaud, Aliette, additional, Charrier, Céline, additional, Pichon, Olivier, additional, Retière, Christelle, additional, Redon, Richard, additional, Pepler, Alexander, additional, McWalter, Kirsty, additional, Da Costa, Lydie, additional, Toutain, Annick, additional, Gleizes, Pierre-Emmanuel, additional, Baud’huin, Marc, additional, and Isidor, Bertrand, additional

Published
2019
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43. Loss of miR-198 and -206 during primary tumor progression enables metastatic dissemination in human osteosarcoma

Author

Georges, Steven, primary, Calleja, Lidia Rodriguez, additional, Jacques, Camille, additional, Lavaud, Melanie, additional, Moukengue, Brice, additional, Lecanda, Fernando, additional, Quillard, Thibaut, additional, Gabriel, Marta Tellez, additional, Cartron, Pierre-François, additional, Baud’huin, Marc, additional, Lamoureux, François, additional, Heymann, Dominique, additional, and Ory, Benjamin, additional

Published
2018
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44. Novel RANK Antagonists for the Treatment of Bone-Resorptive Disease: Theoretical Predictions and Experimental Validation

Author

Téletchéa , Stéphane, Stresing , Verena, Hervouet , Soizic, Baud'Huin , Marc, Heymann , Marie-Françoise, Bertho , Gildas, Charrier , Céline, Ando , Kosei, Heymann , Dominique, Heymann, Dominique, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), This study was supported by the Fond Unique Interministeriel n°08 90 6214 (GELTOP project) and the Ligue Nantionale Contre le Cancer (Equipe LIGUE 2012). K. Ando received a postdoctoral fellowship from the Region des Pays de La Loire (France)., Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques ( LCBPT - UMR 8601 ), and Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
Receptor Activator of Nuclear Factor-kappa B, PEPTIDE INHIBITORS, Ovariectomy, Amino Acid Motifs, RANK Ligand, Drug Evaluation, Preclinical, RANKL, Osteoclasts, Reproducibility of Results, [SDV.CAN]Life Sciences [q-bio]/Cancer, Protective Agents, BONE RESORPTION, Models, Biological, RANK, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, Inbred C57BL, Radiography, [SDV.CAN] Life Sciences [q-bio]/Cancer, Animals, Humans, Computer Simulation, Female, DRUG DESIGN, Peptides, Signal Transduction
Abstract

International audience; Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody-based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure- and knowledge-based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone disease.

Published
2014

46. Abstract 4472: Targeting the oncogenic transcription factor EWS-Fli1 by BET bromodomain inhibition in Ewing sarcoma

Author

JACQUES, Camille, primary, LAMOUREUX, François, additional, BAUD’HUIN, Marc, additional, RODRIGUEZ-CALLEJA, Lidia, additional, QUILLARD, Thibaut, additional, PERROT, Pierre, additional, TIRODE, Franck, additional, REDINI, Françoise, additional, BRADNER, James E., additional, HEYMANN, Dominique, additional, and ORY, Benjamin, additional

Published
2016
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48. ΔNp63α Silences a miRNA Program to Aberrantly Initiate a Wound-Healing Program That Promotes TGFβ-Induced Metastasis

Author

Rodriguez Calleja, Lidia, primary, Jacques, Camille, additional, Lamoureux, François, additional, Baud'huin, Marc, additional, Tellez Gabriel, Marta, additional, Quillard, Thibaut, additional, Sahay, Debashish, additional, Perrot, Pierre, additional, Amiaud, Jerome, additional, Charrier, Celine, additional, Brion, Regis, additional, Lecanda, Fernando, additional, Verrecchia, Franck, additional, Heymann, Dominique, additional, Ellisen, Leif W., additional, and Ory, Benjamin, additional

Published
2016
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49. Blocking HSP90 Addiction Inhibits Tumor Cell Proliferation, Metastasis Development, and Synergistically Acts with Zoledronic Acid to Delay Osteosarcoma Progression

Author

Ory, Benjamin, primary, Baud'huin, Marc, additional, Verrecchia, Franck, additional, Royer, Bénédicte Brounais-Le, additional, Quillard, Thibaut, additional, Amiaud, Jérôme, additional, Battaglia, Séverine, additional, Heymann, Dominique, additional, Redini, Francoise, additional, and Lamoureux, Francois, additional

Published
2016
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50. Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1

Author

Jacques, Camille, primary, Lamoureux, François, additional, Baud’huin, Marc, additional, Calleja, Lidia Rodriguez, additional, Quillard, Thibaut, additional, Amiaud, Jérôme, additional, Tirode, Franck, additional, Rédini, Françoise, additional, Bradner, James E., additional, Heymann, Dominique, additional, and Ory, Benjamin, additional

Published
2016
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