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Crosstalk between pancreatic cancer cells and pancreatic cancer-associated fibroblasts through cytokines and a GPCR


Pancreatic cancer is the third leading cause of cancer death in the United States. Pancreatic ductal adenocarcinoma is the most prevalent type of pancreatic cancer and is characterized by dense fibrosis (termed desmoplasia) in the tumor microenvironment. Cancer associated fibroblasts (CAFs), which are thought to derive from pancreatic stellate cells (PSCs) and fibroblasts (PFs), play a large part in this desmoplasia. Signaling from cancer cells activates CAFs, which in turn can signal to promote tumorigenesis. Previous work done in the Insel lab had identified a GPCR, Orphan 1, as one of the most highly up-regulated GPCRs in CAFs compared to normal PSCs and PFs. This thesis project identifies TGFβ and TNFα as factors that, increase, respectively, the expression in PSCs of fibrotic markers and Orphan 1. Other work in this project shows that Orphan 1 in CAFs regulates the expression and secretion of Interleukin-6 (IL-6). Orphan 1 signals through a Gs-coupled pathway (via cAMP and protein kinase A [PKA]) to increase IL-6 formation and secretion by CAFs; IL-6 can aid in the development of PDAC. Thus, inhibiting the secretion of IL-6 through Orphan 1 may be a novel strategy for the treatment of pancreatic cancer.

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