Abstract PR09: KRas modulates pancreatic cancer cell metabolism and invasive potential through the lipase HSL
Authors: Rozeveld Cody , Schulze Ryan , Zhang Lizhi , Razidlo Gina L 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 9%, due in part to its robust metastatic capability. Metastatic invasion is a particularly energy-intensive cellular process; thus, novel therapeutic strategies could include targeting the energy source for tumor cell invasion and migration. Excess lipids, present due to increased fatty acid synthesis or obesity, could provide a fuel source for cancer progression and metastasis. Neutral lipids are stored in organelles called lipid droplets (LDs). How LDs contribute to PDAC tumor cell invasion and metastasis remains unknown. We hypothesize that PDAC cells can store excess lipid to drive metastatic invasion. Indeed, introduction of excess exogenous fatty acids augments LD production and accumulation in PDAC cells and leads to enhanced PDAC cell motility and invasion in vitro. LDs are metabolized by the concerted action of lipases. Importantly, we have found that treatment of tumor cells with lipase inhibitors blocks tumor cell invasion, indicating that utilization of stored lipids via lipase-mediated LD breakdown is required for invasive migration. Hormone sensitive lipase (HSL) is a lipolytic enzyme, best characterized in adipose tissue, that is critical to the breakdown and utilization of LDs in vitro and in vivo. We have made the surprising observation that oncogenic KRas downregulates expression of HSL in pancreatic cancer cells, which shifts the cells towards lipid storage. In PDAC, mutational activation of the oncogene KRas occurs in 95% of tumors and contributes to metabolic rewiring of tumor cells. Our data suggest that the metabolic shift induced by mutant KRas is comprised of decreased LD utilization via downregulation of HSL. Indeed, re-expression of HSL shifts tumor cell metabolism towards elevated oxidative phosphorylation. Importantly, KRas-mutant cells still require the catalytic activity of HSL for tumor cell invasion, even though HSL expression is downregulated. Using redox ratio imaging, we have found that migratory cells selectively utilize oxidative phosphorylation during the process of migration to metabolize stored lipid droplets and fuel invasive migration. Finally, depletion of LD stores via overexpression of HSL blocks tumor cell invasion in vitro and metastasis in mice, even in the context of oncogenic KRas. These data indicate that regulation of HSL is important for both lipid storage and maintaining cancer cell invasiveness. Therefore, we propose a novel mechanism by which oncogenic KRas mediates HSL activity in a tunable manner, thereby altering the metabolism of PDAC cells and leading to increased metastatic ability.
This abstract is also being presented as Poster B47.
Citation Format: Cody Rozeveld, Ryan Schulze, Lizhi Zhang, Gina L Razidlo. KRas modulates pancreatic cancer cell metabolism and invasive potential through the lipase HSL [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 PR09.