RT Journal Article
SR Electronic
T1 H3K27me3 is a determinant of chemotolerance in triple-negative breast cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.04.423386
DO 10.1101/2021.01.04.423386
A1 Justine Marsolier
A1 Pacôme Prompsy
A1 Adeline Durand
A1 Anne-Marie Lyne
A1 Camille Landragin
A1 Amandine Trouchet
A1 Sabrina Tenreira Bento
A1 Almut Eisele
A1 Sophie Foulon
A1 Léa Baudre
A1 Kevin Grosselin
A1 Mylène Bohec
A1 Sylvain Baulande
A1 Ahmed Dahmani
A1 Laura Sourd
A1 Eric Letouzé
A1 Elisabetta Marangoni
A1 Leïla Perié
A1 Céline Vallot
YR 2021
UL http://biorxiv.org/content/early/2021/01/04/2021.01.04.423386.abstract
AB Triple-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.Competing Interest StatementThe authors have declared no competing interest.