My lab opened in 2009 endowed with the challenge to define the critical regulators of tumor cell response to drugs targeting EGFR (Astsaturov, Science Signaling, 2010). From this initial task which ultimately led to 2 clinical trials in patients with head and neck and lung cancers, 3 NIH grants and 6 papers, we define a previously overlooked step of C4-demethylation in the enzymatic cascade of cholesterol biosynthesis. Inactivation of SC4MOL or NSDHL involved in the oxidative demethylation at C4 leads to dramatic alteration in the vesicular trafficking of the endocytosed EGFR and sensitizes cancer cells to EGFR inhibitors (Sukhanova et al., Cancer Discovery, 2013).

Following this initial lead, Linara Gabitova took on the challenge to pinpoint the mechanism executing such a dramatic effect of accumulating C4-methylated sterols. She found that LXR alpha was the critical effector triggered by these sterol species, so that activation of LXR can be used to deregulate cholesterol turnover in cancer synergistically with EGFR antagonists in in the KRAS-driven tumors (Cell Reports, 2015).

Dr. Gabitova-Cornell next developed a mouse model of pancreatic cancer to study the role of mevalonate pathway in pancreatic carcinogenesis (Cancer Cell, 2020). She discovered a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). In her novel mouse model, disruption of distal cholesterol biosynthesis by conditional inactivation of the rate limiting enzyme Nsdhl, or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras^G12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1 enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests activation of TGFβ signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote basal type of PDAC conferring poor outcomes in patients.

In an ongoing productive collaboration with a partnering laboratory of Dr. Edna Cukierman, we have begun in-depth analyses of the role cancer-associated fibroblasts (CAFs) in pancreatic cancer. We are currently investigating the role of CAFs in providing tumor cells with essential lipids such as cholesterol and other membrane lipid particles. This project led by a postdoctoral fellow, Dr. Charline Ogier, is aimed to develop new strategies to disrupt CAF-cancer cell interactions. We are looking for metabolic vulnerabilities in the cholesterol pathway as well as developing innovative drug delivery tools to improve lives of the patient with this devastating and thus far recalcitrant cancer.