1. H3K27me3 conditions chemotolerance in triple-negative breast cancer
- Author
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Justine Marsolier, Pacôme Prompsy, Adeline Durand, Anne-Marie Lyne, Camille Landragin, Amandine Trouchet, Sabrina Tenreira Bento, Almut Eisele, Sophie Foulon, Léa Baudre, Kevin Grosselin, Mylène Bohec, Sylvain Baulande, Ahmed Dahmani, Laura Sourd, Eric Letouzé, Anne-Vincent Salomon, Elisabetta Marangoni, Leïla Perié, Céline Vallot, Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Recherche Translationnelle, Institut Curie [Paris], Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Chimie-Biologie-Innovation (UMR 8231) (CBI), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), HiFiBiO Therapeutics SAS [Paris], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Plateforme de Séquençage ADN haut débit [Institut Curie] (NGS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Génétique et Biologie du Développement, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the ATIP Avenir program, by Plan Cancer, by the SiRIC-Curie program SiRIC Grants #INCa-DGOS-4654 and #INCa-DGOS-Inserm_12554, and by a starting ERC grant from the H2020 program #948528-ChromTrace (to CV), and by the Fondation de France #00107944 (to JM). The work was supported by an ATIP-Avenir grant from CNRS and Bettencourt-Schueller Foundation, by a starting ERC grant from the H2020 program #758170-Microbar (to LP). And by the SiRIC-Curie program SiRIC Grant #INCa-DGOS- 4654., ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Perié, Leïla, Des cellules aux tissus: au croisement de la Physique et de la Biologie - - CelTisPhyBio2011 - ANR-11-LABX-0038 - LABX - VALID, Equipements d'excellence - Equipement de biologie intégrative du cancer pour une médecine personnalisée - - ICGex2010 - ANR-10-EQPX-0003 - EQPX - VALID, and Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID
- Subjects
Histones ,[SDV] Life Sciences [q-bio] ,Breast cancer ,Drug Resistance, Neoplasm ,Lysine ,[SDV]Life Sciences [q-bio] ,Genetics ,Humans ,Triple Negative Breast Neoplasms ,Epigenetics ,Neoplasm Recurrence, Local ,Methylation - Abstract
International audience; The persistence of cancer cells resistant to therapy remains a major clinical challenge. In triple-negative breast cancer, resistance to chemotherapy results in the highest recurrence risk among breast cancer subtypes. The drug-tolerant state seems largely defined by nongenetic features, but the underlying mechanisms are poorly understood. Here, by monitoring epigenomes, transcriptomes and lineages with single-cell resolution, we show that the repressive histone mark H3K27me3 (trimethylation of histone H3 at lysine 27) regulates cell fate at the onset of chemotherapy. We report that a persister expression program is primed with both H3K4me3 (trimethylation of histone H3 at lysine 4) and H3K27me3 in unchallenged cells, with H3K27me3 being the lock to its transcriptional activation. We further demonstrate that depleting H3K27me3 enhances the potential of cancer cells to tolerate chemotherapy. Conversely, preventing H3K27me3 demethylation simultaneously to chemotherapy inhibits the transition to a drug-tolerant state, and delays tumor recurrence in vivo. Our results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy.
- Published
- 2022
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