Evolutionarily Conserved Epigenetic Regulation of Transcriptional Cell States During Vertebrate Pancreatic Tumorigenesis

BACKGROUND & AIMS: Although the majority of human pancreatic cancers are classified as pancreatic ductal adenocarcinomas, tumors are comprised of diverse dedifferentiated tumor cell states that dynamically interact with an equally complex microenvironment, making it imperative to understand, in vivo, how normal epithelial identity is (dys)regulated during tumorigenesis. METHODS: Here, we integrate data from mouse and human pancreatic ductal adenocarcinoma with a unique zebrafish model of pancreatic cancer to elucidate evolutionarily conserved mechanisms regulating dedifferentiation during pancreatic tumorigenesis. RESULTS: adult zebrafish revealed mixed populations of progenitor-like cells with acinar features, progenitor-like cells with ductal features and undifferentiated progenitor-like cells, providing the opportunity to interrogate specific transcriptional and epigenetic modifiers controlling neoplastic pancreatic cellular differentiation. Screening a panel of chromatin modifiers and chromatin readers for differential expression in these distinct cell clusters revealed hdac9b to be upregulated in the progenitor-like cells enriched for ductal features. RNA velocity trajectories supported an acinar cell-of-origin for these hdac9b-expressing progenitor-like cells. The treatment of fish with the class IIA histone deacetylase inhibitor TMP195 confirmed a functional role of histone deacetylase activity in regulating neoplastic cell differentiation through repression of the ductal-like and progenitor cell states and the associated reactivation of acinar gene expression. Cross-species analyses in autochthonous murine tumors confirmed an early, evolutionarily conserved role for Hdac9 in pancreatic tumorigenesis, marking tumor cell subpopulations characterized by a loss of epithelial differentiation and a basal subtype identity. In human pancreatic cancer, higher HDAC9 expression is significantly correlated with poorly differentiated tumor histology and predicts shorter overall survival in patients with pancreatic ductal adenocarcinoma with classical subtype-enriched tumors. CONCLUSIONS: These findings suggest a highly conserved role for HDAC9 and class IIA histone deacetylases in vertebrate pancreatic tumorigenesis and may lead to new strategies for reactivating (normal acinar-epithelial) differentiation programs to intercept and treat pancreatic ductal adenocarcinoma.