- BBSRB B377
- Lab: B0316-23
My laboratory studies the role of de novo lipogenesis in colorectal cancer (CRC) initiation and progression. A large number of preclinical studies, including ours, have demonstrated that Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is a critical component of tumor cell survival and proliferation for a wide range of cancers, making it an attractive target for cancer therapy.
Using tissue microarray analysis, our group demonstrated that an increased expression of FASN is associated with higher CRC stage. Our studies are the first to demonstrate the importance of FASN upregulation in the development of CRC metastasis. We showed that shRNA-mediated inhibition of FASN significantly reduced lung and hepatic metastases in nude mice and inhibited angiogenesis in an orthotopic CRC mouse model. Our recent work suggests that overexpression of FASN promotes a metabolic switch that fuels bioenergetic pathways to enhance cancer cell survival and support metastasis, particularly under energy stress conditions. More importantly, we showed that even in the presence of exogenous fatty acids CRC cells preferentially oxidize endogenous fatty acids synthesized by FASN, thus providing further evidence of the crucial role of de novo lipid synthesis in CRC progression.
Current research projects in the laboratory has on the following goals:
1. To determine the functional importance of FASN in patient-derived xenograft (PDX) models. We utilize PDX models established from resected human CRC tissues to determine the effect of a novel FASN inhibitor (3V-Biosciences) on tumor growth as a monotherapy or in combination with other therapeutic agents. We utilize targeted next-generation sequencing with a panel of 198 cancer-associated genes to identify mutational profiles of tumors and correlate them to the response to FASN-targeted therapy. Identified “driver mutations” are also used to guide the choices of targeted therapies. We use stable isotope-resolved metabolomics (SIRM) analysis to evaluate the effect of FASN inhibition on tumor metabolism in vivo. Our goal is to identify a subset of patients that would benefit from FASN-targeted therapy and ascertain unique metabolic vulnerabilities and genetic biomarkers that can further guide the development of targeted therapies for CRC.
2. To elucidate the molecular mechanisms of regulation of metastasis by FASN-mediated alteration of sphingolipid metabolism. We found that inhibition of de novo fatty acid synthesis decreased the level of sphingosine kinases (SPHKs) and their product S1P and selectively altered levels of other sphingolipids in CRC cells. We utilize primary CRC cells and in vivo metastatic models to understand the effect of FASN-mediated sphingolipid metabolism on CRC metastasis, and mass spectrometry-based targeted metabolomics to delineate the effect of FASN on sphingolipid composition in CRC cells.
3. To determine the role of CD36 in CRC. We found that membrane localization of CD36, a fatty acid translocase, is associated with metastatic CRC and expression/localization of CD36 is regulated by the level of FASN expression. We utilize PDX models, primary CRC cells, human CRC specimens, and multiple molecular biology techniques including the CRISPR–Cas gene-editing system to understand the role of CD36 and determine the mechanisms of its regulation by FASN in this disease. We also investigate the role of CD36 in developing resistance to FASN Inhibition.
4. To elucidate the effect of FASN on CRC initiation and progression using genetically modified mouse models. We utilize C57BL/6J-ApcMin and FASN/Apc/Cre mouse models to determine the effect of FASN and diet on tumor initiation and progression and animal survival.
Rostov State University
BS Biology, Chemistry Minor, Teacher Certification
North Caucasus Personnel Center
BBA, Business & Public Administration
University of Kentucky
Department of Biomedical Pharmacology
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