Abstract A24: Gene expression along the glycolysis-cholesterol synthesis axis and outcome in pancreatic cancer

Abstract

Abstract Reprogramming of metabolic pathways allows cancer cells to survive and thrive in the tumor microenvironment. Glycolysis-inducing factors including oncogenic KRAS mutations, loss of function in TP53 and hypoxia are prevalent in PDAC. Cholesterol and its metabolites support tumor cell growth and the mevalonate pathway, which uses glycolysis products for de novo cholesterol synthesis, has been found to be upregulated in cancer. However, whether intertumoral heterogeneity in these metabolic networks influences outcome in pancreatic cancer has not been well established. We profiled the expression of glycolytic and cholesterogenic genes in 325 resected and metastatic pancreatic ductal adenocarcinoma (PDAC) tumors and identified four distinct subgroups: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable and metastatic disease settings. Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of these oncogenes. The mitochondrial uptake of pyruvate, the end product of glycolysis, facilitates the generation of acetyl-CoA for cholesterol synthesis. PDAC tumors with a glycolytic gene signature had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of reported prognostic PDAC subtype classifier genes. Our results indicate that PDAC tumors have unique metabolic profiles that influence disease outcome and provide functional correlate to previously identified subtypes. The findings also raise the possibility of a shift in balance between the glycolytic and cholesterogenic pathways as a factor in PDAC progression and a potential target for therapy. Citation Format: Joanna M. Karasinska, James T. Topham, Steve E. Kalloger, Gun Ho Jang, Robert E. Denroche, Luka Culibrk, Laura M. Williamson, Hui-li Wong, Michael K.C. Lee, Grainne M. O'Kane, Richard A. Moore, Andrew J. Mungall, Malcolm J. Moore, Cassia Warren, Andrew Metcalfe, Faiyaz Notta, Jennifer J. Knox, Steven Gallinger, Janessa Laskin, Marco A. Marra, Steven J.M. Jones, Daniel J. Renouf, David F. Schaeffer. Gene expression along the glycolysis-cholesterol synthesis axis and outcome in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A24.