Abstract A34: Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC

The basement membrane (BM) is a predominant microenvironmental factor of the precancerous exocrine pancreas, and evidence suggests that the BM functions not only as a barrier to tumor cell invasion but also as an active tumor-suppressing signaling substrate. However, the molecular underpinnings of such a mechanism have not been resolved. Here we explore the expression and function of the prominent BM receptor dystroglycan (DG) in the normal pancreas and pancreatic disease. We show that DG is highly expressed in the acinar compartment of the normal pancreas; however, there is a strong suppression of DG expression with acinar-to-ductal metaplasia (ADM) in chronic pancreatitis and in all stages of pancreatic cancer evolution, from ADM to neoplasias to adenocarcinoma. The conditional knockout of DG in the murine pancreas produced no evidence of developmental or functional deficiency. However, deletion of DG expression in the context of oncogenic Kras expression (p48-Cre;KrasG12D) led to a clear acceleration of disease, including accelerated PanIN formation and an increased incidence of adenocarcinoma and metastases. Disease acceleration was accompanied by neoplasias with a strongly cystic morphology. These data establish DG as a potent suppressor of pancreatic neoplasias and cancers, and one that is muted in chronic pancreatitis and at the earliest stages of oncogenic transformation. We conclude that DG is a key mediator of the tumor-suppressing functions of the normal BM, and that maintenance or restoration of DG function is a potential target for the delay or prevention of pancreatic cancer evolution. Citation Format: Ge Huang, Christian Lanciault, Rosalie Sears, John Muschler. Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A34.