Project 466854

Pancreatic ductal adenocarcinoma (PDAC) is a major class of pancreatic cancers that accounts for more than 90% of diagnosed cases. Fast progression, late-stage diagnosis, and drug resistance are among factors that make PDAC an aggressive and difficult cancer to treat. Autophagy is an intracellular degradative pathway that is widely considered a driving force for PDAC survival and treatment resistance. Our recent work has suggested that high levels of GABARAPL2 (an autophagy-related protein) in PDAC could reflect enhanced treatment response and improved survival outcomes in PDAC patients treated with adjuvant chemotherapy. The objectives of this current project are to first confirm that GABARAPL2 levels are similarly associated with treatment response in experimental models of PDAC and second, to investigate if modulating GABARAPL2 levels have a direct impact on the observed effects. To manipulate GABARAPL2 expression levels, I will introduce additional copies of the GABARAPL2 gene and also suppress or inactivate the expression of endogenous GABARAPL2. Next the drug concentrations required to reduce the viability of PDAC cells will be deduced. Conventional 2D cell culture models will be used alongside 3D organoid models to better mimic actual PDAC tumors. Together, these studies are expected to help guide treatment strategies for PDAC patients--specifically, to uncover potential molecular mechanisms of treatment resistance and to identify those who may present a clinical benefit in receiving adjuvant chemotherapy versus those who may not.