127 results on '"Mohamed Bentires-Alj"'
Search Results
2. Live slow-frozen human tumor tissues viable for 2D, 3D, ex vivo cultures and single-cell RNAseq
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Gaetana Restivo, Aizhan Tastanova, Zsolt Balázs, Federica Panebianco, Maren Diepenbruck, Caner Ercan, Bodgan-T. Preca, Jürg Hafner, Walter P. Weber, Christian Kurzeder, Marcus Vetter, Simone Münst Soysal, Christian Beisel, Mohamed Bentires-Alj, Salvatore Piscuoglio, Michael Krauthammer, and Mitchell P. Levesque
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Biology (General) ,QH301-705.5 - Abstract
Fresh vs. slow-frozen tissues from various malignancies are compared for the establishment of 2D, 3D and ex vivo cultures, as well as for scRNAseq analysis, and found to be comparable and suitable for cancer research.
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- 2022
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3. ERK3/MAPK6 dictates CDC42/RAC1 activity and ARP2/3-dependent actin polymerization
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Katarzyna Bogucka-Janczi, Gregory Harms, Marie-May Coissieux, Mohamed Bentires-Alj, Bernd Thiede, and Krishnaraj Rajalingam
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ERK3 ,MAPK ,RhoGTPases ,actin polymerization ,Arp2/3 ,cell shape /migration ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding-proteins and nucleation-promoting factors to perform fundamental cellular functions. We have previously shown that ERK3, an atypical MAPK, controls IL-8 production and chemotaxis (Bogueka et al., 2020). Here, we show in human cells that ERK3 directly acts as a guanine nucleotide exchange factor for CDC42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent RAC1 and CDC42 activation, maintenance of F-actin content, filopodia formation, and epithelial cell migration. Further, ERK3 protein bound directly to the purified ARP2/3 complex and augmented polymerization of actin in vitro. ERK3 kinase activity was required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions.
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- 2023
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4. Feed‐forward loops between metastatic cancer cells and their microenvironment—the stage of escalation
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Zora Baumann, Priska Auf der Maur, and Mohamed Bentires‐Alj
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breast cancer ,feed‐forward loops ,interdependency ,metastasis ,tumor microenvironment ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer‐related deaths. While survival of early‐stage breast cancer patients has increased dramatically, the 5‐year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed‐forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue‐specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.
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- 2022
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5. Microbiota-induced tissue signals regulate ILC3-mediated antigen presentation
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Frank Michael Lehmann, Nicole von Burg, Robert Ivanek, Claudia Teufel, Edit Horvath, Annick Peter, Gleb Turchinovich, Daniel Staehli, Tobias Eichlisberger, Mercedes Gomez de Agüero, Mairene Coto-Llerena, Michaela Prchal-Murphy, Veronika Sexl, Mohamed Bentires-Alj, Christoph Mueller, and Daniela Finke
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Science - Abstract
Group 3 innate lymphoid cells (ILC3s) promote T cell activation in the spleen but suppress it in the gut. Here, the authors show that this distinct regulation is mediated by gut microbiota-induced IL-23 and IFN-γ, respectively, and, along with the article by Rao et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
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- 2020
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6. The NFIB‐ERO1A axis promotes breast cancer metastatic colonization of disseminated tumour cells
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Federica Zilli, Pedro Marques Ramos, Priska Auf der Maur, Charly Jehanno, Atul Sethi, Marie‐May Coissieux, Tobias Eichlisberger, Loïc Sauteur, Adelin Rouchon, Laura Bonapace, Joana Pinto Couto, Roland Rad, Michael Rugaard Jensen, Andrea Banfi, Michael B Stadler, and Mohamed Bentires‐Alj
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Breast cancer ,ERO1A ,metastasis ,NFIB ,VEGFA ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Metastasis is the main cause of deaths related to solid cancers. Active transcriptional programmes are known to regulate the metastatic cascade but the molecular determinants of metastatic colonization remain elusive. Using an inducible piggyBac (PB) transposon mutagenesis screen, we have shown that overexpression of the transcription factor nuclear factor IB (NFIB) alone is sufficient to enhance primary mammary tumour growth and lung metastatic colonization. Mechanistically and functionally, NFIB directly increases expression of the oxidoreductase ERO1A, which enhances HIF1α‐VEGFA‐mediated angiogenesis and colonization, the last and fatal step of the metastatic cascade. NFIB is thus clinically relevant: it is preferentially expressed in the poor‐prognostic group of basal‐like breast cancers, and high expression of the NFIB/ERO1A/VEGFA pathway correlates with reduced breast cancer patient survival.
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- 2021
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7. Cancer cell redirection biomarker discovery using a mutual information approach.
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Kimberly Roche, F Alex Feltus, Jang Pyo Park, Marie-May Coissieux, Chenyan Chang, Vera B S Chan, Mohamed Bentires-Alj, and Brian W Booth
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Medicine ,Science - Abstract
Introducing tumor-derived cells into normal mammary stem cell niches at a sufficiently high ratio of normal to tumorous cells causes those tumor cells to undergo a change to normal mammary phenotype and yield normal mammary progeny. This phenomenon has been termed cancer cell redirection. We have developed an in vitro model that mimics in vivo redirection of cancer cells by the normal mammary microenvironment. Using the RNA profiling data from this cellular model, we examined high-level characteristics of the normal, redirected, and tumor transcriptomes and found the global expression profiles clearly distinguish the three expression states. To identify potential redirection biomarkers that cause the redirected state to shift toward the normal expression pattern, we used mutual information relationships between normal, redirected, and tumor cell groups. Mutual information relationship analysis reduced a dataset of over 35,000 gene expression measurements spread over 13,000 curated gene sets to a set of 20 significant molecular signatures totaling 906 unique loci. Several of these molecular signatures are hallmark drivers of the tumor state. Using differential expression as a guide, we further refined the gene set to 120 core redirection biomarker genes. The expression levels of these core biomarkers are sufficient to make the normal and redirected gene expression states indistinguishable from each other but radically different from the tumor state.
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- 2017
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8. K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.
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Irmgard Hofmann, Andreas Weiss, Gaelle Elain, Maria Schwaederle, Dario Sterker, Vincent Romanet, Tobias Schmelzle, Albert Lai, Saskia M Brachmann, Mohamed Bentires-Alj, Thomas M Roberts, William R Sellers, Francesco Hofmann, and Sauveur-Michel Maira
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Medicine ,Science - Abstract
Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.
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- 2012
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9. A high-throughput drug screen reveals means to differentiate triple-negative breast cancer
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Milica Vulin, Charly Jehanno, Atul Sethi, Ana Luísa Correia, Milan M. S. Obradović, Joana Pinto Couto, Marie-May Coissieux, Maren Diepenbruck, Bogdan-Tiberius Preca, Katrin Volkmann, Priska Auf der Maur, Alexander Schmidt, Simone Münst, Loïc Sauteur, Michal Kloc, Marta Palafox, Adrian Britschgi, Vincent Unterreiner, Olaf Galuba, Isabelle Claerr, Sandra Lopez-Romero, Giorgio G. Galli, Daniel Baeschlin, Ryoko Okamoto, Savas D. Soysal, Robert Mechera, Walter P. Weber, Thomas Radimerski, and Mohamed Bentires-Alj
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Cancer Research ,Cell Line, Tumor ,Estrogen Receptor alpha ,Genetics ,Humans ,Cell Cycle Proteins ,Triple Negative Breast Neoplasms ,Breast ,Molecular Biology ,Cell Proliferation - Abstract
Plasticity delineates cancer subtypes with more or less favourable outcomes. In breast cancer, the subtype triple-negative lacks expression of major differentiation markers, e.g., estrogen receptor α (ERα), and its high cellular plasticity results in greater aggressiveness and poorer prognosis than other subtypes. Whether plasticity itself represents a potential vulnerability of cancer cells is not clear. However, we show here that cancer cell plasticity can be exploited to differentiate triple-negative breast cancer (TNBC). Using a high-throughput imaging-based reporter drug screen with 9 501 compounds, we have identified three polo-like kinase 1 (PLK1) inhibitors as major inducers of ERα protein expression and downstream activity in TNBC cells. PLK1 inhibition upregulates a cell differentiation program characterized by increased DNA damage, mitotic arrest, and ultimately cell death. Furthermore, cells surviving PLK1 inhibition have decreased tumorigenic potential, and targeting PLK1 in already established tumours reduces tumour growth both in cell line- and patient-derived xenograft models. In addition, the upregulation of genes upon PLK1 inhibition correlates with their expression in normal breast tissue and with better overall survival in breast cancer patients. Our results indicate that differentiation therapy based on PLK1 inhibition is a potential alternative strategy to treat TNBC.
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- 2022
10. Author response: ERK3/MAPK6 dictates CDC42/RAC1 activity and ARP2/3-dependent actin polymerization
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Katarzyna Bogucka-Janczi, Gregory Harms, Marie-May Coissieux, Mohamed Bentires-Alj, Bernd Thiede, and Krishnaraj Rajalingam
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- 2023
11. Supplementary Figure 3 from Epithelial Protein-Tyrosine Phosphatase 1B Contributes to the Induction of Mammary Tumors by HER2/Neu but Is Not Essential for Tumor Maintenance
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Mohamed Bentires-Alj, Benjamin G. Neel, Kendra K. Bence, Urs Mueller, Adrian Britschgi, Nicola Aceto, and Kamal K. Balavenkatraman
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PDF File (117K)
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- 2023
12. Supplementary Figure 1 from Epithelial Protein-Tyrosine Phosphatase 1B Contributes to the Induction of Mammary Tumors by HER2/Neu but Is Not Essential for Tumor Maintenance
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Mohamed Bentires-Alj, Benjamin G. Neel, Kendra K. Bence, Urs Mueller, Adrian Britschgi, Nicola Aceto, and Kamal K. Balavenkatraman
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PDF File (337K)
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- 2023
13. Supplementary Figure 2 from Epithelial Protein-Tyrosine Phosphatase 1B Contributes to the Induction of Mammary Tumors by HER2/Neu but Is Not Essential for Tumor Maintenance
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Mohamed Bentires-Alj, Benjamin G. Neel, Kendra K. Bence, Urs Mueller, Adrian Britschgi, Nicola Aceto, and Kamal K. Balavenkatraman
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PDF File (553K)
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- 2023
14. Data from Epithelial Protein-Tyrosine Phosphatase 1B Contributes to the Induction of Mammary Tumors by HER2/Neu but Is Not Essential for Tumor Maintenance
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Mohamed Bentires-Alj, Benjamin G. Neel, Kendra K. Bence, Urs Mueller, Adrian Britschgi, Nicola Aceto, and Kamal K. Balavenkatraman
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Protein-tyrosine phosphatase 1B (PTP1B), a well-established metabolic regulator, plays an important role in breast cancer. Using whole-body PTP1B knockout mice, recent studies have shown that PTP1B ablation delays HER2/Neu-induced mammary cancer. Whether PTP1B plays a cell-autonomous or a noncell-autonomous role in HER2/Neu-evoked tumorigenesis and whether it is involved in tumor maintenance was unknown. We generated mice expressing HER2/Neu and lacking PTP1B specifically in the mammary epithelium. We found that mammary-specific deletion of PTP1B delays the onset of HER2/Neu-evoked mammary tumors, establishing a cell autonomous role for PTP1B in such neoplasms. We also deleted PTP1B in established mouse mammary tumors or depleted PTP1B in human breast cancer cell lines grown as xenografts. PTP1B inhibition did not affect tumor growth in either model showing that neither epithelial nor stromal PTP1B is necessary for tumor maintenance. Taken together, our data show that despite the PTP1B contribution to tumor onset, it is not essential for tumor maintenance. This suggests that PTP1B inhibition could be effective in breast tumor prevention. Mol Cancer Res; 9(10); 1377–84. ©2011 AACR.
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- 2023
15. Figure S4 from Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes
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Paul F. Lambert, Dustin A. Deming, Mohamed Bentires-Alj, Dominique S. Meyer, Evie Carchman, Kristina A. Matkowskyj, Andrea Bilger, Susan Payne, and Myeong-Kyun Shin
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Figure S4. Examination of the change of the change in differentiation /maturation by treatment of TAK-228
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- 2023
16. Supplementary methods from Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes
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Paul F. Lambert, Dustin A. Deming, Mohamed Bentires-Alj, Dominique S. Meyer, Evie Carchman, Kristina A. Matkowskyj, Andrea Bilger, Susan Payne, and Myeong-Kyun Shin
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Supplementary methods
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- 2023
17. Supplementary Table 1 from Mammary Tumor Formation and Metastasis Evoked by a HER2 Splice Variant
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Mohamed Bentires-Alj, Debora Bonenfant, Hans Voshol, Sophie Sarret, Stephan Duss, Nicola Aceto, Nina Sausgruber, and Abdullah Alajati
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PDF file, 104K, List of peptides differentially phosphorylated in MCF10A-Delta-HER2 cells compared to WT-HER2.
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- 2023
18. Supplementary Data from Luminal Expression of PIK3CA Mutant H1047R in the Mammary Gland Induces Heterogeneous Tumors
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Mohamed Bentires-Alj, Robert D. Cardiff, Matthias Müller, Urs Müller, Heike Brinkhaus, and Dominique S. Meyer
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Supplementary Figures S1-S3; Supplementary Table S1.
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- 2023
19. Supplementary Figures from Mammary Tumor Formation and Metastasis Evoked by a HER2 Splice Variant
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Mohamed Bentires-Alj, Debora Bonenfant, Hans Voshol, Sophie Sarret, Stephan Duss, Nicola Aceto, Nina Sausgruber, and Abdullah Alajati
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PDF file, 246K, Quantification of WT-HER2 or Delta-HER2 and their effect on wound healing (S1); Low level expression of Delta-HER2 induces P-ERK and P-AKT, increases migration and induces mammary tumors (S2); Effect of WT-HER2 and Delta-HER2 expression on MCF10A 3D cultures (S3); Delta-HER2 overexpressing tumors are sensitive to trastuzumab (S4).
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- 2023
20. Supplementary Methods, Figures 1 - 8, Tables 1 - 2 from VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
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Gerhard Christofori, Mohamed Bentires-Alj, Ulrike Hopfer, Karen Cornille, Nathalie Meyer-Schaller, Mahmut Yilmaz, Akiko Kunita, Chantal Heck, Laura Pisarsky, Dorothea C. Gruber, and Anna Fantozzi
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PDF file - 7604K, Supplemental Figure S1 depicts the increased sensitivity of mesenchymal MTdeltaECad cells to salinomycin as compared to epithelial MTflECad cells. Supplemental Figure S2 shows comparable numbers of mesenchymal MTdeltaECad cells and epithelial MTflECad cells injected i.v. trapped in in lungs and no difference in cell proliferation but higher apoptosis of epithelial MTflECad cells in lung outgrowing lung metastasis. Supplemental Figure S3 presents the assessment of VEGF receptor expression, blood vessel maturation and functionality, and tumor cell proliferation and apoptosis in primary tumors formed by mesenchymal MTdeltaECad cells as compared to tumors of epithelial MTflECad cells. Supplemental Figure S4 shows the upregulated expression of pro-angiogenic genes during EMT by gene ontology and direct gene expression analysis. Supplemental Figure S5 shows an efficient siRNA-mediated ablation of VEGF-A expression in mesenchymal MTdeltaECad cells and that the ablation of VEGF-A expression, treatment with the VEGF receptor inhibitor PTK787 or the addition of recombinant VEGF-A do not affect cell proliferation and mammosphere growth of MTdeltaECad cells or MTflECad cells. Supplemental Figure S6 shows that the forced expression of VEGF-A in epithelial MTflECad cells modestly increases the cells' tumorigenicity and significantly induces tumor microvessel density and vessel functionality, it reduces apoptosis but does not affect tumor hypoxia and cell proliferation. Supplemental Figure S7 shows that other VEGF family members are upregulated in their expression during an EMT in vitro and in vivo, yet that they do not affect tumorigenicity of mesenchymal cancer cells. Supplemental Figure S8 demonstrates that VEGF-A in the supernatant of cultured mesenchymal MTdeltaECad cells induces proliferation of human umbilical vein endothelial cells (HUVEC). Supplemental Table I summarizes the flow cytometry analysis of cell surface markers in NMuMG normal murine mammary gland cell line and in the Py2T and MTflECad/MTdeltaECad murine breast cancer cell lines before and after EMT and cultured on plastic or as spheroids. Supplemental Table II presents the differences in cytokine expression between epithelial MTflECad cells and mesenchymal MTdeltaECad cells as determined by cytokine protein array analysis. Supplemental Methods provide experimental details of the general experimental procedures and reagents used in the main text and of the specific methods used to generate the supplemental data.
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- 2023
21. Supplementary Movie 1 from VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
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Gerhard Christofori, Mohamed Bentires-Alj, Ulrike Hopfer, Karen Cornille, Nathalie Meyer-Schaller, Mahmut Yilmaz, Akiko Kunita, Chantal Heck, Laura Pisarsky, Dorothea C. Gruber, and Anna Fantozzi
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MOV file - 9405K, Three-dimensional confocal reconstitution.
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- 2023
22. Supplementary Movie 2 from VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
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Gerhard Christofori, Mohamed Bentires-Alj, Ulrike Hopfer, Karen Cornille, Nathalie Meyer-Schaller, Mahmut Yilmaz, Akiko Kunita, Chantal Heck, Laura Pisarsky, Dorothea C. Gruber, and Anna Fantozzi
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MPG file - 3174K, Three-dimensional confocal reconstitution.
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- 2023
23. Data from VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
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Gerhard Christofori, Mohamed Bentires-Alj, Ulrike Hopfer, Karen Cornille, Nathalie Meyer-Schaller, Mahmut Yilmaz, Akiko Kunita, Chantal Heck, Laura Pisarsky, Dorothea C. Gruber, and Anna Fantozzi
- Abstract
An epithelial–mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A–mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation. Cancer Res; 74(5); 1566–75. ©2014 AACR.
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- 2023
24. Supplementary Table 2 from Mammary Tumor Formation and Metastasis Evoked by a HER2 Splice Variant
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Mohamed Bentires-Alj, Debora Bonenfant, Hans Voshol, Sophie Sarret, Stephan Duss, Nicola Aceto, Nina Sausgruber, and Abdullah Alajati
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PDF file, 66K, WT-HER2 or Delta-HER2 revealed a specific set of genes that were upregulated in MCF10A-Delta-HER2 cells.
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- 2023
25. Thirteenth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer
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Alecia-Jane Twigger, Jakub Sumbal, Mohamed Bentires-Alj, Beatrice A Howard, Twigger, Alecia-Jane [0000-0003-4361-817X], Sumbal, Jakub [0000-0003-3700-4518], Bentires-Alj, Mohamed [0000-0001-6344-1127], Howard, Beatrice A [0000-0002-9162-0314], and Apollo - University of Cambridge Repository
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Organoids ,Patient-derived Xenografts ,Mammary Gland Biology ,Cancer Research ,Breast cancer ,Oncology ,ductal carcinoma in situ ,Breast Development ,Resistance To Endocrine Therapy ,Lactation ,In Vivo Live Imaging ,Lobular Breast Cancer - Abstract
The thirteenth annual workshop of the European Network for Breast Development and Cancer (ENBDC) Laboratories Annual Workshop took place on the 28–30 April 2022 in Weggis, Switzerland and focused on methods in mammary gland biology and breast cancer. Sixty scientists participated in the ENBDC annual workshop which had not been held in person since 2019 due to the global COVID-19 pandemic. Topics spanned the mammary gland biology field, ranging from lactation biology and embryonic development, single cell sequencing of the human breast, and stunning cutting-edge imaging of the mouse mammary gland and human breast as well as breast cancer research topics including invasive progression of the pre-invasive DCIS stage, metabolic determinants of endocrine therapy resistance, models for lobular breast cancer, and how mutational landscapes of normal breast during age and pregnancy determine cancer risk. The latest findings from participating researchers were presented through oral presentations and poster sessions and included plenty of unpublished work.
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- 2022
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26. Twelfth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer
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Mohamed Bentires-Alj, Elsa Charifou, Beatrice A. Howard, Alexandra Van Keymeulen, and Gunnhildur Asta Traustadottir
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Oncology ,Cancer Research ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Branching ,Mammary gland ,Biology ,Lineage tracing ,Metastasis ,Circulating tumor cell ,Breast cancer ,Internal medicine ,medicine ,Premetastatic niche ,Transcriptomics ,Breast development ,Tumor microenvironment ,Circulating tumor cells ,Cancer ,Tumor dormancy ,medicine.disease ,Signaling ,Organoids ,Patient-derived xenografts ,In vivo live imaging ,medicine.anatomical_structure ,Editorial ,Resistance to therapy - Abstract
The twelfth annual workshop of the European Network for Breast Development and Cancer focused on methods in mammary gland biology and breast cancer, was scheduled to take place on March 26–28, 2020, in Weggis, Switzerland. Due to the COVID-19 pandemic, the meeting was rescheduled twice and eventually happened as a virtual meeting on April 22 and 23, 2021. The main topics of the meeting were branching and development of the mammary gland, tumor microenvironment, circulating tumor cells, tumor dormancy and breast cancer metastasis. Novel and unpublished findings related to these topics were presented, with a particular focus on the methods used to obtain them. Virtual poster sessions were a success, with many constructive and fruitful interactions between researchers and covered many areas of mammary gland biology and breast cancer.
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- 2021
27. Single-cell analysis reveals inter- and intratumour heterogeneity in metastatic breast cancer
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Baptiste Hamelin, Milan Obradović, Atul Sethi, Michal Kloc, Simone Muenst, Christian Beisel, Katja Eschbach, Hubertus Kohler, Savas Soysal, Marcus Vetter, Walter P. Weber, Michael B. Stadler, and Mohamed Bentires-Alj
- Abstract
Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set Enrichment Analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top Differentially Expressed Genes (DEGs) between these cell states revealed a common set of partial EMT Transcriptions Factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.
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- 2022
28. ERK3/MAPK6 dictates Cdc42/Rac1 activity and ARP2/3-dependent actin polymerization
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Katarzyna Bogucka-Janczi, Gregory Harms, Marie-May Coissieux, Mohamed Bentires-Alj, Bernd Thiede, and Krishnaraj Rajalingam
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General Immunology and Microbiology ,General Neuroscience ,General Medicine ,General Biochemistry, Genetics and Molecular Biology - Abstract
The actin cytoskeleton is tightly controlled by RhoGTPases, actin binding-proteins and nucleation-promoting factors to perform fundamental cellular functions. We have previously shown that ERK3, an atypical MAPK, controls IL-8 production and chemotaxis (Bogueka et al., 2020). Here, we show in human cells that ERK3 directly acts as a guanine nucleotide exchange factor for CDC42 and phosphorylates the ARP3 subunit of the ARP2/3 complex at S418 to promote filopodia formation and actin polymerization, respectively. Consistently, depletion of ERK3 prevented both basal and EGF-dependent RAC1 and CDC42 activation, maintenance of F-actin content, filopodia formation, and epithelial cell migration. Further, ERK3 protein bound directly to the purified ARP2/3 complex and augmented polymerization of actin in vitro. ERK3 kinase activity was required for the formation of actin-rich protrusions in mammalian cells. These findings unveil a fundamentally unique pathway employed by cells to control actin-dependent cellular functions.
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- 2022
29. Feed‐forward loops between metastatic cancer cells and their microenvironment—the stage of escalation
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Mohamed Bentires-Alj, Priska Auf der Maur, and Zora Baumann
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Tumor Microenvironment ,Humans ,Molecular Medicine ,Breast Neoplasms ,Female ,Neoplasm Metastasis - Abstract
Breast cancer is the most frequent cancer among women, and metastases in distant organs are the leading cause of the cancer-related deaths. While survival of early-stage breast cancer patients has increased dramatically, the 5-year survival rate of metastatic patients has barely improved in the last 20 years. Metastases can arise up to decades after primary tumor resection, hinting at microenvironmental factors influencing the sudden outgrowth of disseminated tumor cells (DTCs). This review summarizes how the environment of the most common metastatic sites (lung, liver, bone, brain) is influenced by the primary tumor and by the varying dormancy of DTCs, with a special focus on how established metastases persist and grow in distant organs due to feed-forward loops (FFLs). We discuss in detail the importance of FFL of cancer cells with their microenvironment including the secretome, interaction with specialized tissue-specific cells, nutrients/metabolites, and that novel therapies should target not only the cancer cells but also the tumor microenvironment, which are thick as thieves.
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- 2022
30. Phenotypic Plasticity during Metastatic Colonization
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Charly Jehanno, Milica Vulin, Veronica Richina, Federica Richina, and Mohamed Bentires-Alj
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Epithelial-Mesenchymal Transition ,Neoplasms ,Cell Plasticity ,Humans ,Cell Biology ,Neoplasm Metastasis ,Adaptation, Physiological - Abstract
Most solid cancer-related deaths result from metastasis, a multistep process in which cancer cells exit the primary site, intravasate into the bloodstream, extravasate, and colonize distant organs. Colonization is facilitated by clonal selection and the high phenotypic plasticity of cancer cells that creates reversible switching of cellular states. Cancer cell plasticity leads to intratumor heterogeneity and fitness, yielding cells with molecular and cellular programs that facilitate survival and colonization. While cancer cell plasticity is sometimes limited to the process of epithelial-to-mesenchymal transition (EMT), recent studies have broadened its definition. Plasticity arises from both cell-intrinsic and cell-extrinsic factors and is a major obstacle to efficacious anti-cancer therapies. Here, we discuss the multifaceted notion of cancer cell plasticity associated with metastatic colonization.
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- 2022
31. Protein Tyrosine Phosphatase SHP$_2$ Controls Interleukin-8 Expression in Breast Cancer Cells
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Romain J. Amante, Priska Auf der Maur, Veronica Richina, Atul Sethi, Vytautas Iesmantavicius, Debora Bonenfant, Nicola Aceto, and Mohamed Bentires-Alj
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Cancer Research ,Microenvironment ,Proteome ,IL-8 ,ETS1 ,Interleukin-8 ,Breast Neoplasms ,PTPN11 ,Breast cancer ,Cytokines ,CXCL8 ,MAPK ,Phosphatase ,SHP2 ,Oncology ,Cell Line, Tumor ,Humans ,Tyrosine ,Female ,Transcription Factors - Abstract
Treatment of metastasis remains a clinical challenge and the majority of breast cancer-related deaths are the result of drug-resistant metastases. The protein tyrosine phosphatase SHP2 encoded by the proto-oncogene PTPN11 promotes breast cancer progression. Inhibition of SHP2 has been shown to decrease metastases formation in various breast cancer models, but specific downstream effectors of SHP2 remain poorly characterized. Certain cytokines in the metastatic cascade facilitate local invasion and promote metastatic colonization. In this study, we investigated cytokines affected by SHP2 that could be relevant for its pro-tumorigenic properties. We used a cytokine array to investigate differentially released cytokines in the supernatant of SHP2 inhibitor-treated breast cancer cells. Expression of CXCL8 transcripts and protein abundance were assessed in human breast cancer cell lines in which we blocked SHP2 using shRNA constructs or an allosteric inhibitor. The impact of SHP2 inhibition on the phospho-tyrosine-proteome and signaling was determined using mass spectrometry. From previously published RNAseq data (Aceto et al. in Nat. Med. 18:529–37, 2012), we computed transcription factor activities using an integrated system for motif activity response analysis (ISMARA) (Balwierz et al. in Genome Res. 24:869–84, 2014). Finally, using siRNA against ETS1, we investigated whether ETS1 directly influences CXCL8 expression levels. We found that IL-8 is one of the most downregulated cytokines in cell supernatants upon SHP2 blockade, with a twofold decrease in CXCL8 transcripts and a fourfold decrease in IL-8 protein. These effects were also observed in preclinical tumor models. Analysis of the phospho-tyrosine-proteome revealed that several effectors of the mitogen-activated protein kinase (MAPK) pathway are downregulated upon SHP2 inhibition in vitro. MEK1/2 inhibition consistently reduced IL-8 levels in breast cancer cell supernatants. Computational analysis of RNAseq data from SHP2-depleted tumors revealed reduced activity of the transcription factor ETS1, a direct target of ERK and a transcription factor reported to regulate IL-8 expression. Our work reveals that SHP2 mediates breast cancer progression by enhancing the production and secretion of the pro-metastatic cytokine IL-8. We also provide mechanistic insights into the effects of SHP2 inhibition and its downstream repercussions. Overall, these results support a rationale for targeting SHP2 in breast cancer., Journal of Mammary Gland Biology and Neoplasia, 27 (2)
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- 2022
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32. The Eleventh ENBDC Workshop: Advances in Technology Help to Unveil Mechanisms of Mammary Gland Development and Cancerogenesis
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Vida Vafaizadeh, Mohamed Bentires-Alj, Zuzana Koledova, Walid T. Khaled, Marja L. Mikkola, and Emilia Peuhu
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Proteomics ,Societies, Scientific ,0301 basic medicine ,Cancer Research ,Carcinogenesis ,Mammary gland ,Morphogenesis ,Breast Neoplasms ,Genomics ,Computational biology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Breast ,Tumor microenvironment ,Breast development ,Cancer ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Female ,Signal Transduction - Abstract
The eleventh annual workshop of the European Network for Breast Development and Cancer, Methods in mammary gland biology and breast cancer, took place on the 16th to 18th of May 2019 in Weggis, Switzerland. The main topics of the meeting were high resolution genomics and proteomics for the study of mammary gland development and cancer, breast cancer signaling, tumor microenvironment, preclinical models of breast cancer, and tissue morphogenesis. Exciting novel findings in, or highly relevant to, mammary gland biology and breast cancer field were presented, with insights into the methods used to obtain them. Among others, the discussed methods included single-cell RNA sequencing, genetic barcoding, lineage tracing, spatial transcriptomics, optogenetics, genetic mouse models and organoids.
- Published
- 2019
33. Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes
- Author
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Mohamed Bentires-Alj, Dustin A. Deming, Dominique S. Meyer, Myeong Kyun Shin, Andrea Bilger, Paul F. Lambert, Susan N. Payne, Evie Carchman, and Kristina A. Matkowskyj
- Subjects
0301 basic medicine ,Cancer Research ,Carcinogenesis ,Class I Phosphatidylinositol 3-Kinases ,9,10-Dimethyl-1,2-benzanthracene ,Transgene ,Primary Cell Culture ,Mutant ,Anal Canal ,DMBA ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,neoplasms ,Gene ,PI3K/AKT/mTOR pathway ,Benzoxazoles ,Human papillomavirus 16 ,Kinase ,TOR Serine-Threonine Kinases ,Neoplasms, Experimental ,Anus Neoplasms ,Pyrimidines ,030104 developmental biology ,Oncology ,Gain of Function Mutation ,030220 oncology & carcinogenesis ,Carcinogens ,Cancer research ,Female ,Signal Transduction - Abstract
Purpose: Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found. Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), encoded by the Pik3ca gene, are detected in approximately 20% of human anal cancers. Experimental Design: We asked if common activating mutations in Pik3ca contribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA). Mice expressing in their anal epithelium one of two activating mutations in Pik3ca genes, Pik3caH1047R or Pik3caE545K, were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes. Results: Both mutant forms of Pik3ca increased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers. The combination of HPV16 oncogenes and Pik3ca mutations led to anal cancers even in the absence of treatment with DMBA. We further observed that the investigational mTOR1/2 dual inhibitor, TAK-228, significantly reduced the size of anal cancer-derived tumor spheroids in vitro and reduced the growth rates of anal cancer-derived tumor grafts in vivo. Conclusions: These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.
- Published
- 2019
34. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
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Ryoko Okamoto, Luigi Terracciano, Mohamed Bentires-Alj, Marcel P. Trefny, Marcus Vetter, Alfred Zippelius, Joao C. Guimaraes, Walter P. Weber, Katrin Volkmann, Christian Kurzeder, Duvini De Silva, Ana Luísa Correia, Alexander Schmidt, Kirsten D. Mertz, Sandro Bruno, and Priska Auf der Maur
- Subjects
0301 basic medicine ,Chemokine ,Multidisciplinary ,medicine.medical_treatment ,Cancer ,Immunotherapy ,Biology ,medicine.disease ,CXCR4 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cell quiescence ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,biology.protein ,Hepatic stellate cell ,Dormancy ,Cancer dormancy - Abstract
The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1–3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver—a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth. Liver-resident natural killer (NK) cells sustain the dormancy of disseminated breast cancer cells, and a decrease in NK cells and increase in activated hepatic stellate cells is associated with the formation of liver metastases.
- Published
- 2021
35. Microbiota-induced tissue signals regulate ILC3-mediated antigen presentation
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Mairene Coto-Llerena, Nicole von Burg, Edit Horvath, Daniela Finke, Daniel Staehli, Christoph Mueller, Gleb Turchinovich, Mercedes Gomez de Agüero, Tobias Eichlisberger, Frank M. Lehmann, Mohamed Bentires-Alj, Robert Ivanek, Claudia Teufel, Michaela Prchal-Murphy, Veronika Sexl, and Annick Peter
- Subjects
0301 basic medicine ,Transcription, Genetic ,T-Lymphocytes ,Cell ,General Physics and Astronomy ,mTORC1 ,Lymphocyte Activation ,Interleukin-23 ,Mice ,0302 clinical medicine ,Intestinal mucosa ,Interferon ,Lymphocytes ,Phosphorylation ,Promoter Regions, Genetic ,skin and connective tissue diseases ,lcsh:Science ,610 Medicine & health ,Antigen Presentation ,Principal Component Analysis ,Multidisciplinary ,Microbiota ,Innate lymphoid cell ,Cell Polarity ,Nuclear Proteins ,Cell biology ,medicine.anatomical_structure ,Phenotype ,Mucosal immunology ,medicine.drug ,STAT3 Transcription Factor ,T cell ,Science ,Antigen presentation ,T cells ,Antigen-Presenting Cells ,Down-Regulation ,Innate lymphoid cells ,Biology ,Mechanistic Target of Rapamycin Complex 1 ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Interferon-gamma ,Antigen ,SDG 3 - Good Health and Well-being ,Antigens, CD ,medicine ,Animals ,RNA, Messenger ,Interleukins ,Histocompatibility Antigens Class II ,General Chemistry ,Immunity, Innate ,body regions ,030104 developmental biology ,Trans-Activators ,570 Life sciences ,biology ,lcsh:Q ,Spleen ,030215 immunology - Abstract
Although group 3 innate lymphoid cells (ILC3s) are efficient inducers of T cell responses in the spleen, they fail to induce CD4+ T cell proliferation in the gut. The signals regulating ILC3-T cell responses remain unknown. Here, we show that transcripts associated with MHC II antigen presentation are down-modulated in intestinal natural cytotoxicity receptor (NCR)− ILC3s. Further data implicate microbiota-induced IL-23 as a crucial signal for reversible silencing of MHC II in ILC3s, thereby reducing the capacity of ILC3s to present antigen to T cells in the intestinal mucosa. Moreover, IL-23-mediated MHC II suppression is dependent on mTORC1 and STAT3 phosphorylation in NCR− ILC3s. By contrast, splenic interferon-γ induces MHC II expression and CD4+ T cell stimulation by NCR− ILC3s. Our results thus identify biological circuits for tissue-specific regulation of ILC3-dependent T cell responses. These pathways may have implications for inducing or silencing T cell responses in human diseases., Group 3 innate lymphoid cells (ILC3s) promote T cell activation in the spleen but suppress it in the gut. Here, the authors show that this distinct regulation is mediated by gut microbiota-induced IL-23 and IFN-γ, respectively, and, along with the article by Rao et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
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- 2020
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36. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
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Ana Luísa, Correia, Joao C, Guimaraes, Priska, Auf der Maur, Duvini, De Silva, Marcel P, Trefny, Ryoko, Okamoto, Sandro, Bruno, Alexander, Schmidt, Kirsten, Mertz, Katrin, Volkmann, Luigi, Terracciano, Alfred, Zippelius, Marcus, Vetter, Christian, Kurzeder, Walter Paul, Weber, and Mohamed, Bentires-Alj
- Subjects
Proteomics ,Mice, Inbred BALB C ,Liver Neoplasms ,Breast Neoplasms ,Mice, SCID ,Neoplasms, Experimental ,Chemokine CXCL12 ,Coculture Techniques ,Killer Cells, Natural ,Interferon-gamma ,Mice ,Mice, Inbred NOD ,Cell Line, Tumor ,Hepatic Stellate Cells ,Tumor Microenvironment ,Animals ,Humans ,Female ,Immunotherapy ,Neoplasm Metastasis ,Transcriptome - Abstract
The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment
- Published
- 2019
37. Author Correction: Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy
- Author
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Alexander Schmidt, Joao C. Guimaraes, Christian Kurzeder, Marcus Vetter, Mohamed Bentires-Alj, Alfred Zippelius, Duvini De Silva, Kirsten D. Mertz, Ana Luísa Correia, Walter P. Weber, Marcel P. Trefny, Sandro Bruno, Luigi Terracciano, Katrin Volkmann, Ryoko Okamoto, and Priska Auf der Maur
- Subjects
Multidisciplinary ,Breast cancer ,medicine.anatomical_structure ,business.industry ,Cell ,Hepatic stellate cell ,Cancer research ,Medicine ,Dormancy ,Cancer Microenvironment ,business ,medicine.disease - Published
- 2021
38. Reply to: Hippo signalling maintains ER expression and ER+ breast cancer growth
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Adrian Britschgi, Mohamed Bentires-Alj, and Joana Pinto Couto
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Multidisciplinary ,Breast cancer ,Text mining ,Signalling ,Er breast cancer ,Hormone receptor ,business.industry ,Cancer research ,Medicine ,business ,medicine.disease - Published
- 2021
39. Glucocorticoids promote breast cancer metastasis
- Author
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Nenad Manevski, Baptiste Hamelin, Hubertus Kohler, Marie-May Coissieux, Joana Pinto Couto, Alexander Schmidt, Mohamed Bentires-Alj, Ryoko Okamoto, Simone Münst, Atul Sethi, Milan M. S. Obradović, Faculty of Pharmacy, and Division of Pharmaceutical Chemistry and Technology
- Subjects
0301 basic medicine ,Lung Neoplasms ,Tumour heterogeneity ,TUMOR HETEROGENEITY ,INHIBITION ,Breast Neoplasms ,Receptor Tyrosine Kinase-like Orphan Receptors ,Dexamethasone ,Metastasis ,PATHWAY ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Glucocorticoid receptor ,Breast cancer ,Receptors, Glucocorticoid ,Cell Line, Tumor ,REVEALS ,Medicine ,Animals ,Humans ,Neoplasm Metastasis ,Receptor ,Survival rate ,Glucocorticoids ,Mice, Inbred BALB C ,Multidisciplinary ,RECEPTOR ,business.industry ,WOMEN ,QUANTIFICATION ,medicine.disease ,3. Good health ,Survival Rate ,030104 developmental biology ,317 Pharmacy ,030220 oncology & carcinogenesis ,ROR1 ,Cancer research ,Disease Progression ,GROWTH ,Female ,3111 Biomedicine ,business ,GENOMICS ,Protein Kinases ,Hormone ,Signal Transduction - Abstract
Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy(1-3). Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade(4), remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.
- Published
- 2018
40. Breast Cancer Prevention: Lessons to be Learned from Mechanisms of Early Pregnancy–Mediated Breast Cancer Protection
- Author
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Mohamed Bentires-Alj, Christoph Rochlitz, and Fabienne Meier-Abt
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Breast Neoplasms ,Early pregnancy factor ,Mice ,Breast cancer ,Pregnancy ,Risk Factors ,Internal medicine ,medicine ,Animals ,Humans ,Progenitor cell ,biology ,business.industry ,Incidence (epidemiology) ,Age Factors ,Wnt signaling pathway ,Cell Differentiation ,medicine.disease ,Immunology ,Preventive intervention ,biology.protein ,Female ,business - Abstract
Pregnancy at early, but not late age, has a strong and life-long protective effect against breast cancer. The expected overall increase in breast cancer incidence demands the development of a pharmaceutical mimicry of early-age pregnancy–mediated protection. Recently, converging results from rodent models and women on molecular and cellular mechanisms underlying the protective effect of early-age pregnancy have opened the door for translational studies on pharmacologic prevention against breast cancer. In particular, alterations in Wnt and TGFβ signaling in mammary stem/progenitor cells reveal new potential targets for preventive interventions, and thus might help to significantly reduce the incidence of breast cancer in the future. Cancer Res; 75(5); 803–7. ©2015 AACR.
- Published
- 2015
41. Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases
- Author
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Debora Bonenfant, Nina Sausgruber, Jeffrey Wyckoff, Marie-May Coissieux, Hans Voshol, Nicola Aceto, Adrian Britschgi, Mohamed Bentires-Alj, Cédric Leroy, and Michael B. Stadler
- Subjects
Cancer Research ,medicine.medical_treatment ,Breast Neoplasms ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biology ,Metastasis ,Targeted therapy ,Mice ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,Triple-negative breast cancer ,Phosphoproteomics ,Cancer ,Cell migration ,Cell cycle ,medicine.disease ,3. Good health ,Cell biology ,Neoplasm Proteins ,src-Family Kinases ,Heterografts ,Female ,Neoplasm Transplantation - Abstract
Tumor cell migration has a fundamental role in early steps of metastasis, the fatal hallmark of cancer. In the present study, we investigated the effects of the tyrosine phosphatase, SRC-homology 2 domain-containing phosphatase 2 (SHP2), on cell migration in metastatic triple-negative breast cancer (TNBC), an aggressive disease associated with a poor prognosis for which a targeted therapy is not yet available. Using mouse models and multiphoton intravital imaging, we have identified a crucial effect of SHP2 on TNBC cell motility in vivo. Further, analysis of TNBC cells revealed that SHP2 also influences cell migration, chemotaxis and invasion in vitro. Unbiased phosphoproteomics and biochemical analysis showed that SHP2 activates several SRC-family kinases and downstream targets, most of which are inducers of migration and invasion. In particular, direct interaction between SHP2 and c-SRC was revealed by a fluorescence resonance energy transfer assay. These results suggest that SHP2 is a crucial factor during early steps of TNBC migration to distant organs.
- Published
- 2015
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42. The ninth ENBDC Weggis meeting: growth and in-depth characterisation of normal and neoplastic breast cells
- Author
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Mohamed Bentires-Alj, Katrin E. Wiese, Richard Iggo, Maria dM Vivanco, and Romain J. Amante
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Proteomics ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Oestrogen receptor ,Mammary gland ,Meeting Report ,European Network for Breast Development and Cancer ,Biology ,CRISPR screen ,03 medical and health sciences ,Breast cancer ,Surgical oncology ,parasitic diseases ,Organoid culture ,medicine ,Breast development ,Cancer ,medicine.disease ,Proteogenomics ,030104 developmental biology ,medicine.anatomical_structure ,Cancer research ,Estrogen receptor alpha - Abstract
Mammary gland biologists gathered for the ninth annual workshop of the European Network for Breast Development and Cancer (ENBDC) at Weggis on the shores of Lake Lucerne in March 2017. The main themes were oestrogen receptor alpha signalling, new techniques for mammary cell culture, CRISPR screening and proteogenomics.
- Published
- 2017
43. SHP2 regulates proliferation and tumorigenicity of glioma stem cells
- Author
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Laura Roccograndi, Zev A. Binder, Zhuo Zhang, Ichiro Nakano, Nicola Aceto, Mohamed Bentires-Alj, Donald M. O'Rourke, Logan Zhang, and Nadia Dahmane
- Subjects
0301 basic medicine ,Adult ,Male ,Cancer Research ,Carcinogenesis ,Cellular differentiation ,Cell Culture Techniques ,Protein Tyrosine Phosphatase, Non-Receptor Type 11 ,Protein tyrosine phosphatase ,Biology ,medicine.disease_cause ,Proto-Oncogene Mas ,03 medical and health sciences ,SOX2 ,Cell Line, Tumor ,medicine ,Humans ,Aged ,Cell Proliferation ,Tissue Scaffolds ,Cell growth ,Brain Neoplasms ,SOXB1 Transcription Factors ,Glioma ,Neural stem cell ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Neurology ,Oncology ,Cell culture ,Gene Knockdown Techniques ,Cancer research ,Neoplastic Stem Cells ,Female ,Neurology (clinical) ,Stem cell - Abstract
SHP2 is a cytoplasmic protein tyrosine phosphatase (PTPase) involved in multiple signaling pathways and was the first identified proto-oncogene PTPase. Previous work in glioblastoma (GBM) has demonstrated the role of SHP2 PTPase activity in modulating the oncogenic phenotype of adherent GBM cell lines. Mutations in PTPN11, the gene encoding SHP2, have been identified with increasing frequency in GBM. Given the importance of SHP2 in developing neural stem cells, and the importance of glioma stem cells (GSCs) in GBM oncogenesis, we explored the functional role of SHP2 in GSCs. Using paired differentiated and stem cell primary cultures, we investigated the association of SHP2 expression with the tumor stem cell compartment. Proliferation and soft agar assays were used to demonstrate the functional contribution of SHP2 to cell growth and transformation. SHP2 expression correlated with SOX2 expression in GSC lines and was decreased in differentiated cells. Forced differentiation of GSCs by removal of growth factors, as confirmed by loss of SOX2 expression, also resulted in decreased SHP2 expression. Lentiviral-mediated knockdown of SHP2 inhibited proliferation. Finally, growth in soft-agar was similarly inhibited by loss of SHP2 expression. Our results show that SHP2 function is required for cell growth and transformation of the GSC compartment in GBM.
- Published
- 2017
44. Hippo kinases LATS1/2 control human breast cell fate via crosstalk with ERα
- Author
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Christina Scheel, Zsuzsanna Varga, Michael B. Stadler, Mohamed Bentires-Alj, Sungeun Kim, Daniela Kaup, Kirsten D. Mertz, Adrian Britschgi, Shany Koren, Heike Brinkhaus, Alexandra Vissieres, Ghislain M. C. Bonamy, Joana Pinto Couto, Hans Voshol, Tim Roloff, Stephan Duss, Loren Miraglia, Duvini De Silva, Cédric Leroy, Venkateshwar A. Reddy, Anthony P. Orth, University of Zurich, and Bentires-Alj, Mohamed
- Subjects
0301 basic medicine ,Proteasome Endopeptidase Complex ,medicine.medical_specialty ,Ubiquitin-Protein Ligases ,Cellular differentiation ,610 Medicine & health ,Cell fate determination ,Biology ,Protein Serine-Threonine Kinases ,Article ,03 medical and health sciences ,Breast cancer ,10049 Institute of Pathology and Molecular Pathology ,Internal medicine ,medicine ,Humans ,Cell Lineage ,Genes, Tumor Suppressor ,Hippo Signaling Pathway ,Breast ,Progenitor cell ,skin and connective tissue diseases ,Transcription factor ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,1000 Multidisciplinary ,Hippo signaling pathway ,Multidisciplinary ,Ubiquitin ,Tumor Suppressor Proteins ,Myoepithelial cell ,Estrogen Receptor alpha ,YAP-Signaling Proteins ,Cell Differentiation ,Phosphoproteins ,medicine.disease ,Research Highlight ,3. Good health ,Cell biology ,030104 developmental biology ,Endocrinology ,Proteolysis ,Female ,Stem cell ,Carrier Proteins ,Transcription Factors ,Signal Transduction - Abstract
Cell fate perturbations underlie many human diseases, including breast cancer(1,2). Unfortunately, the mechanisms by which breast cell fate are regulated are largely unknown. The mammary gland epithelium consists of differentiated luminal epithelial and basal myoepithelial cells, as well as undifferentiated stem cells and more restricted progenitors(3,4). Breast cancer originates from this epithelium, but the molecular mechanisms that underlie breast epithelial hierarchy remain ill-defined. Here, we use a high-content confocal image-based short hairpin RNA screen to identify tumour suppressors that regulate breast cell fate in primary human breast epithelial cells. We show that ablation of the large tumour suppressor kinases (LATS) 1 and 2 (refs 5, 6), which are part of the Hippo pathway, promotes the luminal phenotype and increases the number of bipotent and luminal progenitors, the proposed cells-of-origin of most human breast cancers. Mechanistically, we have identified a direct interaction between Hippo and oestrogen receptor-alpha (ER alpha) signalling. In the presence of LATS, ERa was targeted for ubiquitination and Ddb1-cullin4-associated-factor 1 (DCAF1)-dependent proteasomal degradation. Absence of LATS stabilized ERa and the Hippo effectors YAP and TAZ (hereafter YAP/TAZ), which together control breast cell fate through intrinsic and paracrine mechanisms. Our findings reveal a non-canonical (that is, YAP/TAZ-independent) effect of LATS in the regulation of human breast cell fate.
- Published
- 2017
45. Mouse Models of Breast Cancer: Deceptions that Reveal the Truth
- Author
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Joana Pinto Couto and Mohamed Bentires-Alj
- Subjects
Oncology ,medicine.medical_specialty ,Invasive carcinoma ,business.industry ,Disease ,Ductal carcinoma ,Hyperplasia ,medicine.disease ,Malignancy ,Metastasis ,Breast cancer ,Internal medicine ,Ductal carcinoma in situ (DCIS) ,medicine ,skin and connective tissue diseases ,business - Abstract
Breast cancer is the most frequently diagnosed malignancy and results in the highest cancer mortality in women aged 20–59 years worldwide [1]. The disease usually progresses from hyperplasia to ductal carcinoma in situ (DCIS), and subsequently invasive carcinoma and metastasis, the latter accounting for almost all deaths among these patients [2].
- Published
- 2017
46. Mechanism-based cancer therapy: resistance to therapy, therapy for resistance
- Author
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P Ramos and Mohamed Bentires-Alj
- Subjects
Cancer Research ,medicine.medical_treatment ,Cancer therapy ,Cancer ,Mechanism based ,Resistance (psychoanalysis) ,Drug resistance ,Therapeutic resistance ,Pharmacology ,Biology ,Bioinformatics ,medicine.disease ,Targeted therapy ,Drug Resistance, Neoplasm ,Neoplasms ,Tumor Microenvironment ,Genetics ,medicine ,Humans ,Therapeutic failure ,Molecular Targeted Therapy ,Molecular Biology - Abstract
The introduction of targeted therapy promised personalized and efficacious cancer treatments. However, although some targeted therapies have undoubtedly improved prognosis and outcome for specific cancer patients, the recurrent problem of therapeutic resistance subdues present revolutionary claims in this field. The plasticity of tumor cells leads to the development of drug resistance by distinct mechanisms: (1) mutations in the target, (2) reactivation of the targeted pathway, (3) hyperactivation of alternative pathways and (4) cross-talk with the microenvironment. Moreover, the intra-tumor heterogeneity of most tumors can also limit therapeutic response. Interestingly, the early identification of some mechanisms of resistance led to the use of alternative agents that improved clinical benefit, demonstrating that an understanding of the molecular mechanisms driving resistance to specific therapies is of paramount importance. Here we review the most generalized mechanisms of resistance to targeted therapies, together with some experimental strategies employed to identify such mechanisms. Therapeutic failure is not an option and we need to understand the dynamics of tumor adaptation in order to adequately adjust therapies; in essence 'to fight fire with fire'.
- Published
- 2014
47. VEGF-Mediated Angiogenesis Links EMT-Induced Cancer Stemness to Tumor Initiation
- Author
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Mohamed Bentires-Alj, Akiko Kunita, Ulrike Hopfer, Laura Pisarsky, Chantal Heck, Dorothea C. Gruber, Nathalie Meyer-Schaller, Mahmut Yilmaz, Gerhard Christofori, Anna Fantozzi, and Karen Cornille
- Subjects
Vascular Endothelial Growth Factor A ,Cancer Research ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Carcinogenesis ,Angiogenesis ,Breast Neoplasms ,Tumor initiation ,Biology ,Neovascularization ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Cell Line, Tumor ,medicine ,Animals ,030304 developmental biology ,Mice, Inbred BALB C ,0303 health sciences ,Neovascularization, Pathologic ,Cancer ,medicine.disease ,Primary tumor ,3. Good health ,Transplantation ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Neoplastic Stem Cells ,Cancer research ,Female ,medicine.symptom - Abstract
An epithelial–mesenchymal transition (EMT) underlies malignant tumor progression and metastatic spread by enabling cancer cells to depart from the primary tumor, invade surrounding tissue, and disseminate to distant organs. EMT also enriches for cancer stem cells (CSC) and increases the capacity of cancer cells to initiate and propagate tumors upon transplantation into immune-deficient mice, a major hallmark of CSCs. However, the molecular mechanisms promoting the tumorigenicity of cancer cells undergoing an EMT and of CSCs have remained widely elusive. We here report that EMT confers efficient tumorigenicity to murine breast cancer cells by the upregulated expression of the proangiogenic factor VEGF-A and by increased tumor angiogenesis. On the basis of these data, we propose a novel interpretation of the features of CSCs with EMT-induced, VEGF-A–mediated angiogenesis as the connecting mechanism between cancer cell stemness and tumor initiation. Cancer Res; 74(5); 1566–75. ©2014 AACR.
- Published
- 2014
48. Patient-derived Xenograft (PDX) Models In Basic and Translational Breast Cancer Research
- Author
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Aaron McCoy, Michael T. Lewis, François Vaillant, Yizheng Tu, Samuel Aparicio, D Alferez, Carol J. Bult, Valentina Scabia, Jorge S. Reis-Filho, Cathrin Brisken, George Sflomos, Susie Airhart, Peter Kabos, Heidi Dowst, Robert Clarke, Shunqiang Li, Elisabetta Marangoni, Eva González-Suárez, Alana L. Welm, Mohamed Bentires-Alj, Jane E. Visvader, Lacey E. Dobrolecki, Shirong Cai, Richard Iggo, Helen Piwnica-Worms, Funda Meric-Bernstam, Matthew J. Ellis, Geoffrey J. Lindeman, Max S. Wicha, Carol A. Sartorius, Marie-France Poupon, and Fariba Behbod
- Subjects
0301 basic medicine ,Cancer Research ,Treatment response ,Patient privacy ,Translational research ,Breast Neoplasms ,Computational biology ,Mice, SCID ,Bioinformatics ,Article ,Càncer de mama ,Translational Research, Biomedical ,03 medical and health sciences ,Preclinical research ,0302 clinical medicine ,Breast cancer ,Patient-derived xenograft ,Mice, Inbred NOD ,Clinical information ,medicine ,Animals ,Humans ,PDX consortium ,Tumor xenograft ,business.industry ,Immunocompromised/immunodeficient mice ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Heterografts ,Female ,Cancer cell lines ,business ,Neoplasm Transplantation - Abstract
Patient-derived xenograft (PDX) models of a growing spectrum of cancers are rapidly supplanting long-established traditional cell lines as preferred models for conducting basic and translational pre-clinical research. In breast cancer, to complement the now curated collection of approximately 45 long-established human breast cancer cell lines, a newly formed consortium of academic laboratories, currently from Europe, Australia, and North America, herein summarizes data on over 500 stably transplantable PDX models representing all three clinical subtypes of breast cancer (ER+, HER2+, and “Triple-negative” (TNBC)). Many of these models are well-characterized with respect to genomic, transcriptomic, and proteomic features, metastatic behavior, and treatment response to a variety of standard-of-care and experimental therapeutics. These stably transplantable PDX lines are generally available for dissemination to laboratories conducting translational research, and contact information for each collection is provided. This review summarizes current experiences related to PDX generation across participating groups, efforts to develop data standards for annotation and dissemination of patient clinical information that does not compromise patient privacy, efforts to develop complementary data standards for annotation of PDX characteristics and biology, and progress toward “credentialing” of PDX models as surrogates to represent individual patients for use in pre-clinical and co-clinical translational research. In addition, this review highlights important unresolved questions, as well as current limitations, that have hampered more efficient generation of PDX lines and more rapid adoption of PDX use in translational breast cancer research.
- Published
- 2016
49. A tumorigenic actin mutant alters fibroblast morphology and multicellular assembly properties
- Author
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Mohamed Bentires-Alj, Cora-Ann Schoenenberger, Ina Klebba, Ueli Aebi, Roman P. Jakob, Ulrich Blache, Marija Plodinec, Rosmarie Suetterlin, and Unai Silvan
- Subjects
biology ,Membrane ruffling ,Actin remodeling ,Arp2/3 complex ,macromolecular substances ,Cell Biology ,Actin cytoskeleton ,Cell biology ,Actin remodeling of neurons ,Profilin ,Structural Biology ,biology.protein ,MDia1 ,Cytoskeleton - Abstract
Tumor initiation and progression are accompanied by complex changes in the cytoarchitecture that at the cellular level involve remodeling of the cytoskeleton. We report on the impact of a mutant β-actin (G245D-actin) on cell structure and multicellular assembly properties. To appreciate the effects of the Gly245Asp substitution on the organization of the actin cytoskeleton, we examined the polymerization properties of G245D-actin in vitro by pyrene polymerization assays and total internal reflection fluorescence microscopy (TIRF). The mutant actin on its own has a significantly reduced polymerization efficiency compared to native actin but also modifies the polymerization of actin in copolymerization experiments. Comparison of the structure of Rat-2 fibroblasts and a stably transfected derivate called Rat-2-sm9 revealed the effects of G245D-actin in a cellular environment. The overall actin levels in Rat-2-sm9 show a 1.6-fold increase with similar amounts of mutant and wild-type actin. G245D-actin expression renders Rat-2-sm9 cells highly tumorigenic in nude mice. In Rat-2-sm9 monolayers, G245D-actin triggers the formation of extensive membrane ruffles, which is a characteristic feature of many transformed cells. To approximate complex cell-cell and cell-matrix interactions that occur in tumors and might modulate the effects of G245D-actin, we extended our studies to scaffold-free 3D spheroid cultures. Bright field and scanning electron microscopy (SEM) show that Rat-2-sm9 and Rat-2 cells share essential features of spheroid formation and compaction. However, the resulting spheroids exhibit distinct phenotypes that differ mainly in surface structure and size. The systematic comparison of transformed and normal spheroids by SEM provides new insights into scaffold-free fibroblast spheroid formation. © 2013 Wiley Periodicals, Inc.
- Published
- 2013
50. Targeting PI3K, HER2 and the IL-8/JAK2 axis in metastatic breast cancer: Which combination makes the whole greater than the sum of its parts?
- Author
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Mohamed Bentires-Alj, Thomas Radimerski, and Adrian Britschgi
- Subjects
Cancer Research ,Combination therapy ,Receptor, ErbB-2 ,Breast Neoplasms ,Disease ,Drug resistance ,Biology ,Pharmacology ,Models, Biological ,Immunomodulation ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Breast ,Molecular Targeted Therapy ,Interleukin 8 ,Neoplasm Metastasis ,PI3K/AKT/mTOR pathway ,Phosphoinositide-3 Kinase Inhibitors ,Interleukin-8 ,Drug Synergism ,Janus Kinase 2 ,medicine.disease ,Metastatic breast cancer ,Blockade ,Infectious Diseases ,Oncology ,Drug Resistance, Neoplasm ,Cancer research ,Female ,Phosphatidylinositol 3-Kinase ,Human cancer ,Signal Transduction - Abstract
The widespread hyperactivation of the PI3K/mTOR pathway in human cancer has made it a prime target for the treatment of this disease. However, a variety of resistance mechanisms involving (re)activation of the targeted pathway or of parallel survival signaling cascades have limited the clinical success of inhibitors targeting PI3K and/or mTOR. Recent studies delineated new crosstalks between PI3K, HER2, JAK2 and IL-8 signaling, which can explain the limited efficacy of PI3K blockade when inhibitors of this pathway are used as single agents. In this review, we summarize molecular mechanisms of resistance to inhibitors of the PI3K/mTOR pathway, provide an outline of new connections between crucial oncogenic signaling pathways, and discuss the potential of new combination therapy approaches to overcome resistance.
- Published
- 2013
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