UC San Diego

G protein-coupled receptors (GPCRs) are the largest superfamily of membrane receptors and are targeted by more than 30% of FDA-approved drugs. Although there has been limited study of GPCRs in cancer, they may be strategic targets in treating both tumor cells and the supportive microenvironment that is implicated in malignancies such as chronic lymphocytic leukemia (CLL) and pancreatic ductal adenocarcinoma (PDAC). In this thesis research, TaqMan® GPCR arrays were used as an unbiased approach to characterize the GPCR profile of CLL cells and NKtert bone marrow cells, as well as PDAC cells and pancreatic- cancer associated fibroblasts (CAFs). The results revealed that targeting two highly expressed Gs-linked GPCRs, VIPR1 and MC2R, in combination with the dual PDE inhibitor IR284, increased CLL cell death, presumably by increasing cellular cAMP levels. I characterized the GPCR profile of bone marrow NKtert cells and found that cAMP-mediated effects reduce NKtert cell viability and proliferation by modulation of protein kinase A (PKA) and the Exchange Protein activated by cAMP -1 (Epac-1), respectively. I determined that PDAC cells express 73 GPCRs whose expression was shared on three patient tumors, and 55 GPCRs shared between two patient-derived cell lines and two PDAC cell lines. Of these GPCRs, the Class C orphan GPRC5A was found to be the most highly expressed and up- regulated in PDAC cells relative to a normal pancreatic ductal epithelial cell line (HPDE6) and in CAFs compared to pre-fibroblast precursor cells (pancreatic stellate cells, PSC). Transfection of HPDE6 cells with GPRC5A enhanced DNA synthesis in the cells, indicating that GPRC5A may contribute to the malignant phenotype of PDAC and may be a novel therapeutic target for pancreatic cancer. Thus, I was able to characterize the expression of GPCRs in two types of cancer, in both the cancer cells themselves and in cells of their associated microenvironment. The findings provide new insights regarding GPCR expression in cancer and suggest new ways in which cancer cells interact with their surrounding microenvironment