Epithelial tumor cells have an inherent plasticity that allows their adaptation to stressful conditions induced by the tumor microenvironment, oncogene signaling per se, conventional or targeted therapies. Such adaptation contributes to tumor progression and therapeutic failure by: i) favoring resistance to the deleterious effects of stress; ii) reducing stress in return; iii) initiating programs of self-renewal and of phenotypic transitions that lead to tumor relapse and escape. They might also constitute a vulnerability in themselves when their maintenance is required for tumor progression and dissemination. Because tumor stress phenotypes are highly variable, the success of stress targeting strategies relies on our ability to identify core signaling modules that are at the convergence of many stress sensing pathways, and that are pharmacologically tractable.
BCL-2 family proteins fall in that category. The canonical protective activity anti-apoptotic members exert under these conditions relies in great part on one critical binding interface that can be targeted thanks to the identification and clinical development of small-molecules BH3 mimetics. Our team has worked, during the last years, to show that cancer cells (from the breast in particular) occasionally display a phenotype of « BCL-2 dependency ». We have described some of the structural motifs on which this phenotype relies and showed that not all motifs are equally targeted by BH3 mimetics. We have defined mechanisms that link this phenotype to the Rb and p53 tumor pathways, anti-mitotic therapy, some cell autonomous oncogenic signaling pathways and tumor contexts. We have also provided evidence that BCL-2/BCL-xL are valid targets in human breast cancers. To achieve this, we have developed an organotypic ex vivo culture of breast cancer specimen and wired it to a clinical protocol set in the Nantes Angers Cancer Center.
Based on these results and expertise, we intend to, for the next 5 years:
– describe at a whole cell level how BCL-2 proteins build a dynamic network of mutually exclusive protein-protein interactions of differing robustness to promote stress adaptation
– understand whether and how cancer cells adapt, using comprehensive paradigms that take into acount ECM and cancer associated fibroblasts (CAFs) influences
-investigate whether reliance of BCL-2 proteins evolves during dynamic clonal evolution of breast cancers, and whether, conversely, BCL-2 proteins influences such evolution.
The goal of these studies is to identify pathways that promote stress adaptation in breast cancers, contributing to tumor progression and resistance to conventional and targeted therapies. They will lead to the characterization of markers of therapeutic response, and identify novel targets for innovating treatments.
cell survival, non-oncogene addiction, BCL-2 family, breast cancer, translational research, therapeutic targeting
Philippe Juin, DR INSERM
Sophie Barillé-Nion, CR INSERM
Laurent Maillet, CR INSERM
Fabien Gautier, CR ICO
Frédérique Souazé, CR INSERM
Magali Le Breton, MCU
Agnès Basseville, CR contractuelle
Thomas Bonneaud, PhD Student
Jean-Sébastien Frénel, MD, PhD student
Steven Lohard, PharmD, PhD Student
Kevin Louault, PhD Student
Nathalie Bourgeois, IE, CDD
Aurélie Fétiveau, Tech, Univ. Nantes
Equipe médicale associée :
Mario Campone, PU-PH ICO
Pascal Jézéquel, PH ICO
Olivier Kerdraon, PH ICO
Nadège Friquet, Tech ICO
Equipe vétérinaire associée
Jérôme Abadie, MC ONIRIS
Frédérique N’Guyen, MC ONIRIS
Sabine Sévère, IR, ONIRIS
Vuillier C, Lohard S, Allègre J, Kayaci C, King LE, Barillé-Nion S, Braun F, Gautier F, Dubrez L, Gilmore A, Juin PP, Maillet L. E2F1 interacts with BCL-xL and regulates its subcellular localization dynamics to trigger cell death. Embo Report (2017).
Carné Trécesson S, Souazé F, Basseville A, Bernard AC, Pécot J, Lopez J, Bessou M, Sarosiek KA, Letai A, Barillé-Nion S, Valo I, Coqueret O, Guette C, Campone M, Gautier F, Juin PP. BCL-XL directly modulates RAS signalling to favour cancer cell stemness. Nat Commun (2017).
Pécot J, Maillet L, Le Pen J, Vuillier C, Trécesson SC, Fétiveau A, Sarosiek KA, Bock FJ, Braun F, Letai A, Tait SW, Gautier F, Juin PP. Tight Sequestration of BH3 Proteins by BCL-xL at Subcellular Membranes Contributes to Apoptotic Resistance. Cell Rep (2016)
Le Pen J, Maillet L, Sarosiek K, Vuillier C, Gautier F, Montessuit S, Martinou JC, Letaï A, Braun F, Juin P. Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL. CDDis (2016)
Véquaud E, Desplanques G, Jézéquel P, Juin P, Barillé-Nion S. Survivin contributes to DNA repair by homologous recombination in breast cancer cells. Breast Cancer Res Treat. (2016)
Véquaud E, Séveno C, Loussouarn D, Engelhart L, Campone M, Juin P, Barillé-Nion S. YM155 potently triggers cell death in breast cancer cells through an autophagy-NF-kB network. Oncotarget (2015)
Bah N, Maillet L, Ryan J, Dubreil S, Gautier F, Letai A, Juin P, Barillé-Nion S. Bcl-xL controls a switch between cell death modes during mitotic arrest. Cell Death Disease. (2014)
Juin P, Geneste O, Gautier F, Depil S, Campone M. Decoding and unlocking the BCL-2 dependency of cancer cells. Nat Rev Cancer. (2013)
Bertin-Ciftci J, Barré B, Le Pen J, Maillet L, Couriaud C, Juin P, Braun F. pRb/E2F-1-mediated caspase-dependent induction of Noxa amplifies the apoptotic effects of the Bcl-2/Bcl-xL inhibitor ABT-737. Cell Death Differ. (2013)
Braun F, de Carné Trécesson S, Bertin-Ciftci J, Juin P. Protect and serve: Bcl-2 proteins as guardians and rulers of cancer cell survival. Cell Cycle. (2013)
Séveno C, Loussouarn D, Bréchet S, Campone M, Juin P, Barillé-Nion S. γ-Secretase inhibition promotes cell death, Noxa upregulation, and sensitization to BH3 mimetic ABT-737 in human breast cancer cells. Breast Cancer Res. (2012)
Ligue contre le Cancer 44
Ligue contre le Cancer Grand-Ouest
Association de Recherche contre le Cancer
Fondation de France
Région Pays de la Loire
Céline Vuillier : Mitochondrial apoptosis regulated by E2F1. Involvement of the E2F1 mitochondrial targeting and interactions with the Bcl-2 Family anti-apoptotic members (December 2016)
Jessie Pécot : BCLxL dependence of cancer cells. Targeting of the dynamic BCLxL/PUMA/BAX network. Oncogenic pathways regulated by the non canonical RAS/BCLxL interaction (October 2015)
Eloise Véquaud : Study of mammary cancer cells response to silencing of surviving by RNA interference or pharmacological targeting: highlighting oh homologous recombination regulation by surviving. (December 2014)