Obesity has been linked to enhanced cancer mortality across almost all cancer types. Recent studies have provided mechanistic insights into how obesity can contribute to tumorigenesis through enhanced insulin signaling or low-grade inflammation. We have recently also uncovered a potential link between obesity and cancer malignancy in which aggressive cancer cells exhibit heightened levels of free fatty acids which in-turn are transformed into oncogenic signaling lipids, such as lysophosphatidic acid and prostaglandins, which in turn drive aggressive features in cancer. We previously showed that an enzyme, monoacylglycerol lipase (MAGL), upregulated across multiple human aggressive cancer cells and primary tumors, drives this lipolytic release of free fatty acids and that blockin MAGL suppressed fatty acid release and subsequent formation of LPA and prostaglandins leading to suppressed cancer cell aggressiveness and tumor growth. Quite provocatively, however, these defects in cancer pathogenicity were rescued by addition of exogenous fatty acids in vitro or high-fat diet in vivo, giving rise to the intriguing hypothesis that the role of AGL in supplying cancer cells with FFAs can be supplanted by exogenous sources of fat. This remodeling of exogenous fatty acids into either structural or signaling lipid components for the cancer cell requires both fatty acid transport into the cells and enzymatic processes that would incorporate fatty acids units into complex lipids, thereby giving rise to the possibility of targetng these FFA-transport or metabolic pathways for therapeutic intervention to thwart obesity-related effects on cancer. This proposal will map metabolic pathways that remodel dietary fat into protumorigenic signaling lipids to drive cancer malignancy using advanced metabolomic approaches.

Public Health Relevance

Epidemiological studies indicate that adiposity contributes to the increased incidence and/or death from cancers of colon, breast, endometrium, kidney, oesophagus, gastric cardia, pancreas, gallbladders, and liver, and possibly other cancers. This proposal will investigate whether dietary fat can be directly taken up by cancer cells to be remodeled into complex lipids which can in-turn stimulate cancer malignancy and fuel tumorigenicity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA170317-02
Application #
8519390
Study Section
Special Emphasis Panel (ZCA1-SRLB-D (M1))
Program Officer
Spalholz, Barbara A
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$148,982
Indirect Cost
$46,757
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Mulvihill, Melinda M; Benjamin, Daniel I; Ji, Xiaodan et al. (2014) Metabolic profiling reveals PAFAH1B3 as a critical driver of breast cancer pathogenicity. Chem Biol 21:831-40
Hunerdosse, Devon; Nomura, Daniel K (2014) Activity-based proteomic and metabolomic approaches for understanding metabolism. Curr Opin Biotechnol 28:116-26
Mulvihill, Melinda M; Nomura, Daniel K (2014) Metabolomic strategies to map functions of metabolic pathways. Am J Physiol Endocrinol Metab 307:E237-44
Medina-Cleghorn, Daniel; Nomura, Daniel K (2014) Exploring metabolic pathways and regulation through functional chemoproteomic and metabolomic platforms. Chem Biol 21:1171-84
Benjamin, Daniel I; Louie, Sharon M; Mulvihill, Melinda M et al. (2014) Inositol phosphate recycling regulates glycolytic and lipid metabolism that drives cancer aggressiveness. ACS Chem Biol 9:1340-50
Benjamin, Daniel I; Cozzo, Alyssa; Ji, Xiaodan et al. (2013) Ether lipid generating enzyme AGPS alters the balance of structural and signaling lipids to fuel cancer pathogenicity. Proc Natl Acad Sci U S A 110:14912-7
Louie, Sharon M; Roberts, Lindsay S; Mulvihill, Melinda M et al. (2013) Cancer cells incorporate and remodel exogenous palmitate into structural and oncogenic signaling lipids. Biochim Biophys Acta 1831:1566-72