John Harms' Research
Professor of Biology
Pancreatic cancer—specifically pancreatic ductal adenocarcinoma (PDAC)—has an incredibly dismal prognosis. With an average five-year survival of 2-8%, it has recently climbed to the third most common cause of cancer death in the U.S. Pancreatic cancer is typically diagnosed late in its progression when the cancer has already metastasized to regional lymph nodes, liver, and other distant sites, severely curtailing options for surgical resection. Furthermore, it is notoriously resistant to chemotherapy.
Our lab has a longstanding interest in the role of two important gastrointestinal hormones—gastrin and cholecystokinin—in the growth and aggressiveness of pancreatic cancer. Normally, these hormones are produced by the stomach and small intestine to help coordinate digestive functions of the pancreas. However, in pancreatic cancer, the hormones are aberrantly expressed by pancreatic cancer cells themselves and stimulate increased tumor growth in a self-stimulating (autocrine) feedback loop. Additionally, their shared receptor (CCK2R) can be abnormally structured (mis-spliced) in cancers, resulting in a receptor variant correlated with increased tumor growth.
Recent evidence also suggests this hormone signaling may contribute to high fibrosis in the tumor microenvironment. Compared to most tumor types, pancreatic cancers have a uniquely high level of fibrosis—a dense collagen-rich “scar tissue” that can comprise a majority of the tumor mass, collapse blood vessels, limit immune cell access, and inhibit treatment.
Current projects focus on (1) characterizing the role of genetic variations (polymorphisms) in the mis-splicing of the gastrin receptor and expression of various receptor forms in patient tumors, (2) elucidating the specific role of gastrin/cholecystokinin signaling in tumor fibrosis, and (3) determining if drugs used to block this signaling can improve treatment of both established and metastatic pancreatic cancer.