细胞状态可塑性在成人上皮组织中受到精细调控，以预防癌症的发生。在肿瘤中，通常受限的细胞状态可塑性的异常扩张，目前尚不清楚。使用基因工程和致癌物诱导的小鼠肠道肿瘤模型，我们观察到受损的分化是癌症发展之前的共性事件。小鼠模型和遗传性息肉病患者早期病变单细胞RNA测序(scRNA-seq)表明，癌症通过采用异常的转录状态，特征为再生活性的Ly6a (Sca-1)标记和重新激活包括Tacstd2 (Trop2)在内的胎儿肠道基因来启动。Sox9的遗传灭活阻止了腺瘤形成，阻碍了再生和胎儿计划的出现，并通过scRNA-seq恢复了多线age分化。Apc失活导致再生和胎儿基因的扩展染色质可及性降低，伴随Sox9的抑制。这些研究表明，在癌症发展之前，由无节制的再生活性和发育重编程介导的异常细胞状态可塑性先行出现。

Cell state plasticity is carefully regulated in adult epithelia to prevent cancer. The aberrant expansion of the normally restricted capability for cell state plasticity in neoplasia is poorly defined. Using genetically engineered and carcinogen-induced mouse models of intestinal neoplasia, we observed that impaired differentiation is a conserved event preceding cancer development. Single-cell RNA sequencing (scRNA-seq) of premalignant lesions from mouse models and a patient with hereditary polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by regenerative activity, marked by Ly6a (Sca-1), and reactivation of fetal intestinal genes, including Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation, obstructed the emergence of regenerative and fetal programs, and restored multilineage 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.