Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer

Cell state transitions control the functional behavior of cancer cells. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenicity and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput chemical library screens, retinoids are found to be potent promoters of MET that inhibit tumorigenicity in basal-like breast cancer. Cell state transitions are defined by reprogramming of lipid metabolism. Retinoids bind cognate nuclear receptors, which target lipid metabolism genes, thereby redirecting fatty acids for β-oxidation in the mesenchymal cell state towards lipid storage in the epithelial cell state. Disruptions of key metabolic enzymes mediating this flux inhibit MET. Conversely, perturbations to fatty acid oxidation (FAO) rechannel fatty acid flux and promote a more epithelial cell phenotype, blocking EMT-driven breast cancer metastasis in animal models. FAO impinges on the epigenetic control of EMT through acetyl-CoA-dependent regulation of histone acetylation on EMT genes, thus determining cell states.Agency for Science, Technology and Research (A*STAR)Ministry of Education (MOE)National Medical Research Council (NMRC)National Research Foundation (NRF)National University of Singapore (NUS), Temasek LaboratoriesPublished versionThis research is supported by the National Medical Research Council, Singapore (OFIRG17may061, OFIRG19nov-0106, OFYIRG18May-0025, and CTGIIT18may0012); National Research Foundation Singapore (NRF-NRFF2015-04, NRFCRP22-2019-0003, NRF-CRP23-2019-0004, and NRFSBP-P4); National Cancer Institute Singapore Yong Siew Yoon Research Grant; Agency for Science, Technology and Research, Singapore (IAF-ICP I1901E0040); National University of Singapore via the Life Sciences Institute (LSI); and the Singapore Ministry of Education under its Research Centers of Excellence initiative