Laisné Marthe, Lupien Mathieu, Vallot Céline
CNRS UMR3244, Institut Curie, PSL University, Paris, France.
Translational Research Department, Institut Curie, PSL University, Paris, France.
Nat Rev Cancer. 2025 Jan;25(1):7-26. doi: 10.1038/s41568-024-00757-9. Epub 2024 Oct 16.
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.
在过去十年中，通过开发针对DNA序列变异的治疗方法，癌症医学取得了显著进展。然而，由于相同基因型可能产生多种细胞状态，单纯基于基因的治疗选择方法受到了阻碍。在多细胞生物中，细胞状态异质性由调控基于DNA的功能（如转录）的表观遗传过程驱动；这些过程的破坏是癌症的一个标志，它使得有缺陷的细胞状态得以出现。单细胞技术的进步使我们有能力量化肿瘤的表观基因组异质性并了解其机制，从而改变了我们对表观基因组变化如何驱动癌症进化的认识。本综述探讨了这样一种观点，即表观基因组异质性和可塑性充当细胞状态的储存库，因此也是肿瘤进化的一个来源。讨论了量化表观基因组异质性并探索其各种原因和后果的最佳实践，包括表观基因组重编程、随机变化和持久记忆。还讨论了设计新的治疗方法以限制表观基因组异质性，其长期目标是限制癌症的发展和进展。
