Aberrant Glycosylation and Altered FXR Activity Converge to Drive PDA Progression

ASPIRE Award (2021-Present)

Ronald Evans, PhD and Danielle Engle, PhD, Salk Institute

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the US. PDA is highly aggressive, and patients are usually diagnosed late, after the cancer has metastasized and is inoperable. There is a lack of effective treatments for PDA and incidence continues to rise due to its association with obesity, smoking and type 2 diabetes.

Bile acid disruption is commonly observed in pancreatic, esophageal, stomach and colon cancers, and bile acids are also associated with many other PDA risk factors. Interestingly, preliminary data from the Evans and Engle labs suggest that elevated levels of carbohydrate antigen (CA) 19-9 glycosylation directly cause pancreatitis and stimulate remodeling of the pancreatic microenvironment. CA 19-9 primes pancreatic ductal cells for bile acid signaling that acts via the farnesoid X nuclear receptor (FXR). Evans and Engle hypothesize that increased CA 19-9 levels modulate bile acid signaling in the pancreas through reduced FXR expression, which in turn drives PDA progression.

Evans and Engle aim to identify CA 19-9-dependent secreted factors that alter bile acid homeostasis, first in the liver where they will utilize liver organoids. The groups will then go on to investigate the convergence of CA19-9 and FXR in pancreatic tumorigenesis using mouse and human models of PDAC including pancreatic organoids. Elucidating the cellular and molecular mechanisms though which bile acids impact tumor growth has the potential to reveal novel avenues for therapeutic intervention in not only PDA, but also other gastrointestinal malignancies.