小柯机器人

英国弗朗西斯·克里克研究所Paola Scaffidi团队近期取得重要工作进展，他们研究发现表观遗传破坏的癌细胞通过表型惯性的选择优势。这一工作成果2022年11月3日在线发表于《癌细胞》杂志上。

研究人员发现表观遗传调控网络的破坏通过促进抗应激亚群的出现，增加癌细胞对生长肿瘤所经历的不利环境的耐受性。表观遗传控制的破坏不促进遗传定义的亚克隆的选择，也不利于响应环境变化的表型转换。相反，它阻止细胞通过调节整体转录活性建立有效的应激反应。这种“转录麻木”降低早期细胞死亡的概率，增加了群体水平上长期适应的机会。

这一发现为癌症中亚克隆表观遗传相关突变的广泛选择提供了一个机制解释，并揭示了作为一种驱动亚克隆扩展的细胞特征的表型惯性。

据介绍，已确定癌症的进化是由具有增强适应性细胞的选择驱动的。许多表观遗传调节基因的亚克隆突变在癌症类型中很常见，但其功能影响尚不清楚。

附：英文原文

Title: Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia

Author: Ioannis Loukas, Fabrizio Simeoni, Marta Milan, Paolo Inglese, Harshil Patel, Robert Goldstone, Philip East, Stephanie Strohbuecker, Richard Mitter, Bhavik Talsania, Wenhao Tang, Colin D.H. Ratcliffe, Erik Sahai, Vahid Shahrezaei, Paola Scaffidi

Issue&Volume: 2022-11-03

Abstract: The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This “transcriptional numbness” lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.

DOI: 10.1016/j.ccell.2022.10.002

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00493-7

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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