In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency.

Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipid metabolic gene expression. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of fatty acid and cholesterol synthesis genes. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however, it is not understood which lipid metabolic genes are essential for tumorigenesis.Using an in vivo CRISPR knockout screening method, we identified the mevalonate pathway genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identify geranylgeranyldiphosphate (GGPP) as an essential lipid for tumor growth. Additionally, we propose a combination drug treatment to improve cancer cell killing in statin treated PDAC cells that prevents restoration of lipid homeostasis through SREBPs. Our findings suggest that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of cancer cells. To determine the gene expression changes in PDAC cells treated with a statin and SREBP inhibitor, we grew Pa03c cells in lipoprotein deficient medium and treated them for 16 hours and conducted RNA-seq. We included vehicle controls and two biological replicates for each condition and analyzed gene expression changes in each drug treated condition relative to the respective vehicle control.