Myc instructs and maintains pancreatic adenocarcinoma phenotype

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity and dismal prognosis. We show that acute activation of Myc in indolent PanIN epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune cell types and trigger transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch.The study was supported by program grants to G.I.E. (Cancer Research UK C4750/A12077 and C4750/A19013A, European Research Council (294851), and a Stand Up To Cancer-Cancer Research UKLustgarten Foundation Pancreatic Cancer Dream Team Research Grant (Grant Number: SU2C-AACR-DT20-16). Stand Up To Cancer is a division of the Entertainment Industry Foundation and the research grant is administered by the American Association for Cancer Research, the Scientific Partner of SU2C