Cell state (phenotypic) plasticity is a carefully regulated feature of adult epithelial cells that enables adaptive responses to injury, inflammation, and other forms of stress. Aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation is a critical aspect of neoplasia. The nongenetic factors and specific programs that mediate aberrant cell state plasticity and impaired differentiation require deeper characterization to understand this elusive aspect of cancer pathogenesis. Using genetically engineered and carcinogen-induced murine models of intestinal neoplasia, we demonstrate that impaired differentiation is a conserved event preceding cancer development. Single cell RNA-sequencing (scRNA-seq) of neoplastic intestinal lesions from both mouse models and a patient with familial adenomatous polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by nonoverlapping expression of a regenerative pathway, marked by Ly6a (Sca-1), and a fetal intestinal program, positive for Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation in Apc^KO mice, obstructed emergence of aberrant regenerative and fetal intestinal programs, and restored multi-lineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

中文翻译：

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由发育重编程介导的异常细胞状态可塑性先于结直肠癌发生

细胞状态（表型）可塑性是成体上皮细胞的一种精心调控的特征，能够对损伤、炎症和其他形式的压力做出适应性反应。异常扩展通常受限的细胞状态可塑性以逃避终末分化的能力是瘤形成的一个关键方面。介导异常细胞状态可塑性和分化受损的非遗传因素和特定程序需要更深入的表征，以了解癌症发病机制这一难以捉摸的方面。使用基因工程和致癌物诱导的肠肿瘤小鼠模型，我们证明分化受损是癌症发展之前的保守事件。Ly6a (Sca-1) 和胎儿肠道程序，Tacstd2 (Trop2) 呈阳性。Sox9的基因失活阻止了 Apc ^KO小鼠的腺瘤形成，阻碍了异常再生和胎儿肠道程序的出现，并通过 scRNA-seq 恢复了多谱系分化。伴随的 Sox9 抑制减少了 Apc 失活后染色质可及性的扩大和胎儿基因的再生。这些研究表明，由有增无减的再生活动和发育重编程介导的异常细胞状态可塑性先于癌症发展。