Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation. Mus musculus

Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells. Overall design: We used microrrays to identify gene expression profiles and pathways that are differentially activated after conditional expression of an oncogenic form of Kras and deletion of one allele of Prox1 in the pancreas