Defining Roles of Metabolic Reprogramming in Pancreatic Tumorigenesis and Tumor Maintenance

Abstract

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Nearly all pancreatic tumors harbor mutations in oncogenic KRAS. Unfortunately, KRAS is difficult to target therapeutically, despite decades of efforts. As such, KRAS-dependent pathways remain promising targets for the development of new therapeutics. Pancreatic cancer extensively reprograms cellular metabolism to support uncontrolled growth and proliferation. Mutations in oncogenic KRAS drive metabolic rewiring that PDA cells are dependent on to supply biosynthetic precursors and energy. Understanding the metabolic dependencies of tumorigenesis and tumor maintenance could reveal targetable vulnerabilities for disease detection and/or treatment.

Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM), and inhibiting pathways that maintain acinar homeostasis can accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS, and one that we hypothesized was mediated by metabolic rewiring. Transcriptomic analysis revealed global enhancement of metabolic programs in acinar cells undergoing ADM. We previously demonstrated that pancreatic cancer cells rewire glucose and glutamine metabolism to support growth and survival. Using in vitro models of ADM, we found that glutamine availability is not required for ADM. In contrast, glucose availability and intact oxidative phosphorylation are required for ADM. A more detailed analysis of the pathways downstream of glucose metabolism revealed that disrupting the oxidative pentose phosphate pathway accelerates ADM in vitro and tumorigenesis in vivo, likely due to heightened oxidative stress. Changes in redox balance can attenuate or accelerate ADM in vitro and in vivo.

Redox homeostasis is also tightly regulated in pancreatic cancer cells by rewiring glutamine metabolism through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. GOT1 inhibition disrupts redox homeostasis in pancreatic cancer cells. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Understanding the metabolic pathways that contribute to pancreatic tumorigenesis and tumor maintenance, such as redox homeostasis, could provide biomarkers for diagnosis of early disease or development of better therapeutics for treating pancreatic cancer.