Aberrant cell state plasticity mediated by developmental reprogramming precedes colorectal cancer initiation [scRNA-seq]

Cell state plasticity is carefully regulated in adult epithelia, enabling adaptive responses to stressors. The nongenetic factors that control aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation in neoplasia require deeper characterization. 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 intestinal neoplasia from both 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 emergence of regenerative and fetal 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. Overall design: scRNA-seq of mouse models of CRC as well as FAP patients associated with study