Defining the Role of the Hexosamine Biosynthesis Pathway in Pancreatic Cancer

Abstract

Metabolic rewiring is a hallmark of pancreatic ductal adenocarcinomas (PDA), a lethal disease that is notoriously resistant to therapies. This is due in part to the tumor microenvironment, which is largely composed of a dense fibrotic stroma and extracellular matrix. Hyaluronic acid (HA), a linear, carbohydrate polymer and a key component of the extracellular matrix, is a major contributor to the elevated interstitial pressure, resulting in vascular collapse that impedes drug delivery and creates an aberrant nutrient landscape. To survive and proliferate in this environment, pancreatic cancer cells rewire their metabolism and scavenge from the tumor microenvironment. Nearly all pancreatic tumors harbor mutations in oncogenic Kras, which increases the glycolytic flux into the hexosamine biosynthetic pathway (HBP). As such, the HBP potentially represents a metabolic vulnerability that could reveal novel targets for disease treatment. The underlying goal of this thesis is to define the role of HBP in pancreatic cancer. This dissertation provides a comprehensive review on pancreatic cancer metabolism, tumor microenvironment, and the role of HBP in other cancers (Chapter 1). Testing for PDA dependence on the HBP revealed HA as a novel nutrient source that fuels the HBP via the N-acetyl-glucosamine salvage pathway (Chapter 2). Furthermore, future work stemming from preliminary findings will investigate whether inhibition of cell-intrinsic HBP is sufficient to sensitize pancreatic cancer to anti-PD-(L)1 therapy, an immune checkpoint blockade immunotherapy that has not been successful in PDA, despite demonstrating revolutionary success in other cancers (Chapter 3). Finally, this dissertation proposes several future directions: the elucidation of the GlcNAc salvage pathway in more physiologically relevant models, further mechanistic delineation of HA fueling the HBP, and testing whether other non-cancerous cells populating the tumor microenvironment and components of the extracellular matrix can regulate the HBP in cancer cells (Chapter 4).