DNA methylation memory of acinar-ductal transition state altering Kras-downstream Pi3k and Rho GTPase signaling [spatial transcriptomics]

A critical area of recent cancer research is the emergence of transition states between normal and cancer that exhibit increased cell plasticity which underlies tumor cell heterogeneity. Pancreatic ductal adenocarcinoma (PDAC) arises from a transition state termed acinar-to-ductal metaplasia (ADM), in which digestive enzyme-producing acinar cells acquire a transient ductal epithelium-like phenotype while maintaining their geographical acinar organization. ADM is created by overexpression of the Kruppel-like factor 4 gene (KLF4) in the absence of oncogenic driver mutations. Here, we investigate the DNA methylation landscape and corresponding transcriptional landscape of the mutation-free ADM transition state and the subsequent reversion to a normal acinar phenotype. We ask to what extent cells retain a memory of the ADM transition state via DNA methylation, examine potential regulators of altered DNA methylation during ADM, and investigate the relationship of the ADM transition state to human pancreatic cancer precursor lesions. These findings may inform the mechanisms not only of heritable epigenetic memory of transition states and inflammation, but also of how epigenetic alterations presage or even elicit genetic mutations in cancer.