TY - JOUR
T1 - Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance
AU - Lamballe, Fabienne
AU - Ahmad, Fahmida
AU - Vinik, Yaron
AU - Castellanet, Olivier
AU - Daian, Fabrice
AU - Müller, Anna Katharina
AU - Köhler, Ulrike A.
AU - Bailly, Anne Laure
AU - Josselin, Emmanuelle
AU - Castellano, Rémy
AU - Cayrou, Christelle
AU - Charafe-Jauffret, Emmanuelle
AU - Mills, Gordon B.
AU - Géli, Vincent
AU - Borg, Jean Paul
AU - Lev, Sima
AU - Maina, Flavio
N1 - Funding Information:
F.L. and F.A. contributed equally as joint first authors. S.L. and F.M. contributed equally as joint senior authors. The authors thank all members of labs for helpful discussions and comments, R. Dono and F. Helmbacher for extremely valuable feedback on the study, A. Furlan for initial work with mice, S. Richelme for in vivo bioluminescence imaging reported in Figure 1B and for work on a first cohort of mice, E. Marechal for her contribution to the characterization, C. Sequera for the analysis of overall survival of TNBC patients according to expression levels, M. Buferne for in vivo bioluminescence imaging, and the animal house platform for excellent help with mouse husbandry. This research was supported by a grant from the Ministry of Foreign Affairs and International Development (MAEDI) and the Ministry of National Education, Higher Education and Research (MENESR) of France and by the Ministry of Science and Technology of Israel (Grant #3‐14002) to F.M. and S.L. This study was supported in part by research funding from Institut National du Cancer, Région Provence‐Alpes‐Côte d'Azur, and Canceropôle Provence‐Alpes‐Côte d'Azur to F.M. F.A. was supported by the Higher Education Commission (HEC) of Pakistan. U.A.K. was supported by the Rising Tide Foundation Cancer Research Postdoctoral Fellowship, the Dean Fellowship of the Faculty of Biology of the Weizmann Institute of Science (WIS), and the Postdoctoral Fellowship of the Swiss Society of Friends of the WIS. J.‐P.B. is a scholar of Institut Universitaire de France. V.G. was supported by the “Ligue Nationale Contre le Cancer” (Equipe Labellisée). The contribution of the Region Provence Alpes Côtes d'Azur and of the Aix‐Marseille University to the IBDM animal facility and of the France‐BioImaging/PICsL infrastructure (ANR‐10‐INBS‐04‐01) to the imaging facility is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. MMTV‐R26 Met MMTV‐R26 Met MET
Funding Information:
F.L. and F.A. contributed equally as joint first authors. S.L. and F.M. contributed equally as joint senior authors. The authors thank all members of labs for helpful discussions and comments, R. Dono and F. Helmbacher for extremely valuable feedback on the study, A. Furlan for initial work with MMTV-R26Met mice, S. Richelme for in vivo bioluminescence imaging reported in Figure?1B and for work on a first cohort of mice, E. Marechal for her contribution to the MMTV-R26Met characterization, C. Sequera for the analysis of overall survival of TNBC patients according to MET expression levels, M. Buferne for in vivo bioluminescence imaging, and the animal house platform for excellent help with mouse husbandry. This research was supported by a grant from the Ministry of Foreign Affairs and International Development (MAEDI) and the Ministry of National Education, Higher Education and Research (MENESR) of France and by the Ministry of Science and Technology of Israel (Grant #3-14002) to F.M. and S.L. This study was supported in part by research funding from Institut National du Cancer, R?gion Provence-Alpes-C?te d'Azur, and Cancerop?le Provence-Alpes-C?te d'Azur to F.M. F.A. was supported by the Higher Education Commission (HEC) of Pakistan. U.A.K. was supported by the Rising Tide Foundation Cancer Research Postdoctoral Fellowship, the Dean Fellowship of the Faculty of Biology of the Weizmann Institute of Science (WIS), and the Postdoctoral Fellowship of the Swiss Society of Friends of the WIS. J.-P.B. is a scholar of Institut Universitaire de France. V.G. was supported by the ?Ligue Nationale Contre le Cancer? (Equipe Labellis?e). The contribution of the Region Provence Alpes C?tes d'Azur and of the Aix-Marseille University to the IBDM animal facility and of the France-BioImaging/PICsL infrastructure (ANR-10-INBS-04-01) to the imaging facility is also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2020 The Authors. Advanced Science published by Wiley-VCH GmbH
PY - 2021/2/3
Y1 - 2021/2/3
N2 - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
AB - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
KW - BCL-XL
KW - MET
KW - WEE1
KW - cancer mouse model
KW - drug resistance
KW - signaling reprogramming
KW - triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85097633855&partnerID=8YFLogxK
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U2 - 10.1002/advs.202003049
DO - 10.1002/advs.202003049
M3 - Article
AN - SCOPUS:85097633855
SN - 2198-3844
VL - 8
JO - Advanced Science
JF - Advanced Science
IS - 3
M1 - 2003049
ER -