SREBP-Dependent Regulation of Lipid Homeostasis Is Required for Progression and Growth of Pancreatic Ductal Adenocarcinoma.

ABSTRACT

Solid tumors undergo metabolic reprogramming when growth outstrips local nutrient supply. Lipids such as cholesterol and fatty acids are required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of brain, breast, colon, liver, and prostate cancers. However, the role of the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role of Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using xenograft models, we showed that SCAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low-serum conditions because of a lack of lipid supply. Highlighting its clinical importance, the SREBP pathway is broadly required across cancer cell lines, target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets is associated with poor survival in patients with PDAC. Collectively, these results demonstrate that SCAP and SREBP pathway activity are required for PDAC cell and tumor growth, identifying SCAP as a potential therapeutic target for PDAC. SIGNIFICANCE: Our findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.