Highlights in Cancer Research: November 2022

The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).

The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.

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1. H3K27me3 conditions chemotolerance in triple-negative breast cancer

Marsolier J, Prompsy P, et al. Nat Genet. 54(4):459-468. (2022).
doi: 10.1038/s41588-022-01047-6.

Summary of the findings

Persistence of cancer cells 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. Marsolier et al. show that repressive histone modifications – H3K27me3 – condition the ability of a cancer cell to tolerate chemotherapy. Combining single-cell epigenomic and transcriptomic approaches to lineage tracing strategies, authors map the initial epigenomic events driving tolerance to chemotherapy in triple-negative breast cancer in patient-derived xenografts, cell lines and patient samples. They show that the repressive histone mark H3K27me3 is a lock to the activation of a drug-persistent expression program in breast cancers. Under chemotherapy, very few cells can survive the treatment, and these cells have a remodeled repressive epigenome, with targeted loss at key promoters. Using demethylase inhibitor in combination to chemotherapy, they show the possibility to improve response rate and delay recurrence both in vitro and in vivo.

“This paper shows that, at least in triple-negative breast cancer, the H3K27me3 landscape is a key determinant in the development of chemoresistance” EACR Board

At the onset of chemotherapy treatment, the majority of cancer cells die, while a rare fraction of cells can tolerate chemotherapy, so-called persister cells. The epigenome of persister cells is marked by an organized loss of repressive histone marks (H3K27me3) at genes that already poised for activation (decorated with H3K4me3/H3K27me3).

Future impact

These results highlight how chromatin landscapes shape the potential of cancer cells to respond to initial therapy. Locking the plasticity of the cell, here with a demethylase inhibitor, impairs their ability to escape treatment. Understanding epigenomic tumor evolution at single cell resolution was instrumental to design a combinatory treatment scheme to enhance response with an epigenetic compound. Mapping response to treatment in patients will now be essential to further understand the epigenomic evolution of the tumor and its microenvironment in response to various cancer therapies.

Read more in Nature Genetics