H3K27me3 is a determinant of chemotolerance in triple-negative breast cancer
Autor: | Sylvain Baulande, Adeline Durand, Anne-Marie Lyne, Almut S Eisele, Pacôme Prompsy, Camille Landragin, Justine Marsolier, Ahmed Dahmani, Céline Vallot, Kevin Grosselin, Sophie Foulon, Amandine Trouchet, Sabrina Tenreira Bento, Elisabetta Marangoni, Leïla Perié, Mylène Bohec, Laura Sourd, Eric Letouzé, Léa Baudre |
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Přispěvatelé: | Dynamique de l'information génétique : bases fondamentales et cancer (DIG CANCER), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Sorbonne Université (SU), 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) |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0303 health sciences
biology [SDV]Life Sciences [q-bio] Cell fate determination medicine.disease 3. Good health Chromatin Transcriptome 03 medical and health sciences 0302 clinical medicine Histone Breast cancer 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research medicine H3K4me3 Triple-negative breast cancer 030304 developmental biology |
Popis: | SummaryTriple-negative breast cancer is associated with the worst prognosis and the highest risk of recurrence among all breast cancer subtypes1. Residual disease, formed by cancer cells persistent to chemotherapy, remains one of the major clinical challenges towards full cure2,3. There is now consensus that non-genetic processes contribute to chemoresistance in various tumor types, notably through the initial emergence of a reversible chemotolerant state4–6. Understanding non-genetic tumor evolution stands now as a prerequisite for the design of relevant combinatorial approaches to delay recurrence. Here we show that the repressive histone mark H3K27me3 is a determinant of cell fate under chemotherapy exposure, monitoring epigenomes, transcriptomes and lineage with single-cell resolution. We identify a reservoir of persister basal cells with EMT markers and activated TGF-β pathway leading to multiple chemoresistance phenotypes. We demonstrate that, in unchallenged cells, H3K27 methylation is a lock to the expression program of persister cells. Promoters are primed with both H3K4me3 and H3K27me3, and removing H3K27me3 is sufficient for their transcriptional activation. Leveraging lineage barcoding, we show that depleting H3K27me3 alters tumor cell fate under chemotherapy insult – a wider variety of tumor cells tolerate chemotherapy. Our results highlight how chromatin landscapes shape the potential of unchallenged cancer cells to respond to therapeutic stress. |
Databáze: | OpenAIRE |
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