PRJNA480163
Rewiring of lipid metabolism is essential for cell state transitions in breast cancer
Cell state transitions control the functional behavior of cancer cells, including their tumorigenicity and responses to therapeutics. Epithelial-to-mesenchymal transition (EMT) confers cancer stem cell-like properties, enhanced tumorigenic potential, and drug resistance to tumor cells, while mesenchymal-epithelial transition (MET) reverses these phenotypes. Using high-throughput drug library screens, we uncovered retinoids as potent promoters of an MET in basal-like breast cancer cells, including patient-derived tumor cell models, that dramatically inhibit tumorigenicity. Beyond the classic MET marker signatures, we observed a reexpression of luminal characteristics such as estrogen receptor (ER) and mucin, typically associated with ER+ breast tumors, as well as a basal-to-luminal cytokeratin switch, thus priming the triple-negative breast cancer cells to standard-of-care therapies. HDAC inhibitors, through epigenetic remodeling, help increase the potency and durability of the MET phenotype that is induced by retinoids. Strikingly, we revealed that cell state transitions in breast cancer are defined by a reprogramming of their metabolic phenotypes, particularly lipid metabolism. Retinoids, through the retinoic acid receptor (RAR) and retinoid X receptor (RXR), bind and target key lipid metabolism genes. This led to a redirection of the utilization of fatty acids for ß-oxidation in the mesenchymal cell state towards lipid droplet storage in the epithelial cell state. Perturbations to ß-oxidation using the CPT1 inhibitor, etomoxir, rechanneled fatty acid flux and promoted a more epithelial cell phenotype, and furthermore were able to inhibit EMT-driven metastasis in animal models.