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 Ö-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
Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Edinburgh, UK.
Nature. 2025 Jun 4. doi: 10.1038/s41586-025-09125-5.
Cancer cell plasticity enables the acquisition of new phenotypic features and is implicated as a major driver of metastatic progression. Metastasis occurs mostly in the absence of additional genetic alterations, which suggests that epigenetic mechanisms are important. 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.
癌细胞可塑性促使新表型特征的获得，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基因改变的情况下，这表明表观遗传机制很重要。然而，它们仍然定义不清。在此，我们确定染色质重塑酶ATRX是结直肠癌中结肠谱系保真度和转移的关键调节因子。Atrx缺失促进肿瘤侵袭和转移，同时伴随着结肠上皮特征的丧失以及高度可塑性的间充质和鳞状样细胞状态的出现。染色质可及性和增强子图谱的联合分析确定，结肠谱系特异性转录因子HNF4A活性受损是这些观察到的表型的关键介导因素。我们在人类患者样本中鉴定出鳞状样细胞以及与侵袭性疾病和患者预后不良相关的鳞状样表达特征。总体而言，我们的研究将ATRX和HNF4A对结肠上皮特征的表观遗传维持定义为结直肠癌中谱系可塑性和转移的抑制因子。
