Kevin B. Myant小组的一项最新研究报道了结肠保真度的丧失使多系可塑性和转移成为可能。这一研究成果发表在2025年6月4日出版的国际学术期刊《自然》上。

在这里，研究人员发现染色质重塑酶ATRX是结直肠癌结肠谱系保真度和转移的关键调节因子。基质丢失促进肿瘤的侵袭和转移，同时伴有结肠上皮特性的丢失和高度可塑性的间充质和鳞状细胞状态的出现。对染色质可及性和增强子定位的联合分析发现，结肠谱系特异性转录因子HNF4A的活性受损是这些观察到的表型的关键介质。研究团队在人类患者样本中鉴定出鳞状细胞样细胞，以及与侵袭性疾病和不良患者预后相关的鳞状细胞样表达特征。总的来说，他们的研究确定了ATRX和HNF4A对结肠上皮身份的表观遗传维持是结直肠癌谱系可塑性和转移的抑制因子。

据介绍，癌细胞的可塑性能够获得新的表型特征，并被认为是转移进展的主要驱动因素。转移大多发生在没有额外遗传改变的情况下，这表明表观遗传机制很重要。然而，它们的定义仍然很模糊。

附：英文原文

Title: Loss of colonic fidelity enables multilineage plasticity and metastasis

Author: Cammareri, Patrizia, Raponi, Michela, Hong, Yourae, Billard, Caroline V., Peckett, Nat, Zhu, Yujia, Velez-Bravo, Fausto D., Younger, Nicholas T., Dunican, Donnchadh S., Pohl, Sebastian .-G., Bastem Akan, Aslihan, Doleschall, Nora J., Falconer, John, White, Mark, Quinn, Jean, Pennel, Kathryn, Garau, Roberta, Malla, Sudhir B., Dunne, Philip D., Meehan, Richard R., Sansom, Owen J., Edwards, Joanne, Dunlop, Malcolm G., Din, Farhat V. N., Tejpar, Sabine, Steele, Colin W., Myant, Kevin B.

Issue&Volume: 2025-06-04

Abstract: Cancer cell plasticity enables the acquisition of new phenotypic features and is implicated as a major driver of metastatic progression1,2. Metastasis occurs mostly in the absence of additional genetic alterations3,4,5, which suggests that epigenetic mechanisms are important6. However, they remain poorly defined. Here we identify the chromatin-remodelling enzyme ATRX as a key regulator of colonic lineage fidelity and metastasis in colorectal cancer. Atrx loss promotes tumour invasion and metastasis, concomitant with a loss of colonic epithelial identity and the emergence of highly plastic mesenchymal and squamous-like cell states. Combined analysis of chromatin accessibility and enhancer mapping identified impairment of activity of the colonic lineage-specifying transcription factor HNF4A as a key mediator of these observed phenotypes. We identify squamous-like cells in human patient samples and a squamous-like expression signature that correlates with aggressive disease and poor patient prognosis. Collectively, our study defines the epigenetic maintenance of colonic epithelial identity by ATRX and HNF4A as suppressors of lineage plasticity and metastasis in colorectal cancer.

DOI: 10.1038/s41586-025-09125-5

Source: https://www.nature.com/articles/s41586-025-09125-5