The HDL particle composition determines its anti-tumor activity in pancreatic cancer

Abstract

Pancreatic cancer is expected to become the second leading cause of cancer-related deaths in the next decade as a result of late diagnosis, a highly fibrotic tumor microenvironment and rapidly emerging resistance mechanisms. Previous research identified lipid metabolic pathways to be highly enriched in pancreatic ductal adenocarcinoma (PDAC) cells. Thereby, cholesterol uptake and synthesis promoted a growth advantage to, and chemotherapy resistance for PDAC tumor cells. We demonstrate that efficient cholesterol removal from cancer cells by high-density lipoprotein (HDL) mediated efflux, results in a significant PDAC cell growth reduction, apoptosis and a decreased PDAC tumor development in vivo. This effect is driven by an HDL particle composition-dependent interaction with major lipid flux receptors expressed on cancer cells, ABCA1 and SRB1. Eventually, we show that pancreatic cancer patient plasma samples display reduced levels of HDL-cholesterol and reduced cholesterol efflux capacity. Thus, cholesterol depletion from PDAC cells, together with interventions that shunt the import and endogenous synthesis pathways of cholesterol, might represent a promising strategy to increase the currently available treatment options for PDAC patients.