Abstract
In the past decade, remarkable progress in cancer medicine has been achieved by the development of treatments that target DNA sequence variants. However, a purely genetic approach to treatment selection is hampered by the fact that diverse cell states can emerge from the same genotype. In multicellular organisms, cell-state heterogeneity is driven by epigenetic processes that regulate DNA-based functions such as transcription; disruption of these processes is a hallmark of cancer that enables the emergence of defective cell states. Advances in single-cell technologies have unlocked our ability to quantify the epigenomic heterogeneity of tumours and understand its mechanisms, thereby transforming our appreciation of how epigenomic changes drive cancer evolution. This Review explores the idea that epigenomic heterogeneity and plasticity act as a reservoir of cell states and therefore as a source of tumour evolution. Best practices to quantify epigenomic heterogeneity and explore its various causes and consequences are discussed, including epigenomic reprogramming, stochastic changes and lasting memory. The design of new therapeutic approaches to restrict epigenomic heterogeneity, with the long-term objective of limiting cancer development and progression, is also addressed.
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Acknowledgements
The authors thank O. Delattre, F. Gaiti, J. Marsolier and M. Schwartz for critical reading of the manuscript. The authors’ research work is supported by the Canadian Institute of Health Research (grants FRN-153234, FRN-158225, FRN-168933 and FRN-191847 to M. Lupien), the Ontario Institute for Cancer Research Investigator Award through funding provided by the Government of Ontario (IA-031 to M. Lupien), the Princess Margaret Cancer Foundation (to M. Lupien), the Joey and Toby Tanenbaum/Brazilian Ball Chair (to M. Lupien), the Fondation Bettencourt Schueller (to M. Laisné and C.V.), SiRIC-Curie program grants no. INCa-DGOS-4654 and no. INCa-DGOS-INSERM-12554 (to C.V.) and the European Research Council Horizon 2020 program (StG Chromtrace #948528, to C.V.).
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Glossary
- Basin of attraction
-
The set of initial cell states that all cells can reach.
- Chromatin variants
-
Altered chromatin states over nucleosomes or neighbouring nucleosomes with reference epigenomes that define physiological cell states.
- Epi-clones
-
Also known as epigenetic clones. Cells or group of cells with shared heritable chromatin variants.
- Epigenomic heterogeneity
-
The display of different sets of chromatin variants within a given cell population.
- Epigenomic instability
-
The incapacity of cells to maintain the integrity of epigenomic marks over time.
- Epigenomic marks
-
Chemical modifications of chromatin (a DNA and protein complex) that can be either transient or heritable (epigenetic) and define chromatin states based on their combination at the nucleosome or over neighbouring nucleosomes.
- Epigenomic reprogramming
-
Active acquisition of chromatin variants in response to external stimuli, which can adapt gene expression programmes and alter phenotypic states.
- Epigenomic stochasticity
-
Random biological changes to the epigenome of a cell over time that might either be tolerated or lead to changes in cell function.
- Pioneer factors
-
Transcription factors with the unique ability to initiate opening of closed chromatin.
- Pliancy
-
The capacity of a cell to tolerate genetic and/or chromatin variants without altering its state and related functions.
- Potency
-
The capacity of a cell to access multiple gene expression programmes and cell states, which can be estimated through single-cell epigenomics.
- Proteolysis-targeting chimeras
-
(PROTACs). Highly specific bifunctional molecules with two functional moieties connected by a linker that degrade unwanted or harmful proteins in cells.
- Tagmentation
-
A transposome-mediated reaction that combines tagging and DNA fragmentation into a single, rapid reaction.
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Laisné, M., Lupien, M. & Vallot, C. Epigenomic heterogeneity as a source of tumour evolution. Nat Rev Cancer 25, 7–26 (2025). https://doi.org/10.1038/s41568-024-00757-9
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DOI: https://doi.org/10.1038/s41568-024-00757-9
