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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247762 | GEO | 2024/12/31

REPOSITORIES: GEO

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Pancreatic ductal adenocarcinoma tumor growth requires SREBP pathway activity

Project description:Tumor growth outstrips local nutrient supply, making metabolic reprogramming a necessary component of oncogenesis and cancer progression. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell division. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for cholesterol and fatty acid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including glioblastoma, breast, colon, liver and prostate. However, the role 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 demonstrate that SREBP target genes are upregulated in PDAC tumors, and SREBPs are upregulated in patient-derived PDAC cell lines under low serum conditions that mimic the tumor microenvironment. Chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for PDAC tumor growth. Pancreas-specific knockout of Scap had no effect on mouse pancreas development or function, allowing examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap significantly prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor inception. Collectively, these results demonstrate that SCAP and SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC.

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