Abstract C156: GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stromal matrix, composed of activated fibroblasts (PFs)/stellate cells (PSCs), immune/inflammatory cells and other cell types. This unique tumor microenvironment is increasingly recognized as a key mediator of PDAC progression and drug resistance. Targeting the tumor stroma may thus be a therapeutic approach for PDAC. Pancreatic cancer-associated fibroblasts (CAFs), myofibroblast-like cells that produce extracellular matrix proteins, are responsible for the desmoplasia in PDAC. PSCs and PFs are the key progenitors of CAFs. Blocking the activity of CAFs may be a means to improve the therapy and prognosis of PDAC. We hypothesized that G protein-coupled receptors (GPCRs) expressed by pancreatic CAFs are potential therapeutic targets for PDAC. To begin to test this hypothesis, we used an unbiased GPCRomic array approach to identify and quantify the GPCRs expressed by pancreatic CAFs. We discovered that 104 GPCRs have shared expression in CAFs from the primary tumors of five patients; 35 of those GPCRs had at least a 2-fold increased expression in CAFs compared to both PSCs and PFs. An orphan GPCR that we term Orphan 1 is one of the most highly up-regulated GPCRs in CAFs. We found that: 1) co-culture of PSCs with a PDAC cell line (ASPC-1) increases expression of fibrotic markers and Orphan 1 GPCR; 2) Transfection of Orphan 1 GPCR in PSCs increases the expression of fibrotic markers; 3) siRNA knockdown of Orphan 1 in CAFs decreases fibrotic marker expression and cytokine secretion. We conclude that GPCRomics can identify GPCRs that regulate pancreatic CAFs. One such GPCR, Orphan 1, contributes to pro-fibrotic activities in CAFs and is a potential therapeutic target to blunt the fibrosis associated with pancreatic cancer. Citation Format: Shu Zhou, Sarah Chang, Thalia McCann, Randall French, Andrew M. Lowy, Paul A. Insel. GPCRs as potential therapeutic targets in pancreatic cancer-associated fibroblasts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C156.