Collagen XVII Promotes Pancreatic Ductal Adenocarcinoma Tumor Growth through Regulation of PIK3R5.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly chemoresistant malignancy with a dismal 11% 5-year survival rate. PDAC tumors are composed of a dense desmoplastic stroma, and the interaction of this collagen-rich tumor microenvironment with PDAC cells promotes their aggressive growth and metastatic spread. In this study, we investigated the role of collagen XVII, a unique transmembrane collagen that connects the extracellular matrix to cytoplasmic signaling complexes. Examination of PDAC tumors revealed that its expression is an independent prognostic biomarker associated with worsened oncological outcomes. Xenograft tumor studies and in vitro coculture experiments with PDAC cell lines and immortalized cancer-associated fibroblasts defined a critical role for the tumor microenvironment in mediating the expression of collagen XVII in the cancer compartment of PDAC tumors. Genetic depletion of collagen XVII reduces the viability and migration of PDAC cells in vitro and orthotopic tumor formation in vivo, underscoring its critical role in PDAC tumor biology. Tumors formed by collagen XVII-depleted PDAC cells exhibit a dramatic downregulation of phosphoinositide 3-kinase regulatory subunit 5, a regulatory subunit of the class I phosphatidylinositol 3-kinase (PI3K) γ complex, and decreased levels of downstream activated AKT. Taken together, these findings reveal collagen XVII signaling as a novel target for PDAC treatment and provide insight into the mechanisms by which it regulates PI3K activity.

Significance: Our study highlights the importance of cross-talk between the tumor microenvironment and PDAC cells in mediating the expression of a key signaling pathway responsible for PI3K activity in PDAC cells.