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The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36+ metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36+ metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
The mechanisms whereby some tumour cells detach from the primary lesion to colonize distant sites are still largely unknown. Pro-metastatic events common to the majority of solid tumours might include the reversible transition of tumour cells from an epithelial to a mesenchymal state as well as their interactions with stromal components or tumour-activated stromal cells1-17. Some tumours also secrete metastasis-promoting exosomes that contain proteins, mRNAs and microRNAs to establish a distant pro-metastatic niche9,13,18,19. However, whether a subpopulation of metastasis-initiating cells exists among primary tumour-initiating cells is not clear.
LRCs express lipid metabolism genes
When cell lines and patient-derived cells (PDCs) arising from human oral carcinomas (Methods) were pulsed with a lipophilic fluorescent dye (DiD) that non-specifically binds to membranes and is diluted upon cell division20, and were orthotopically injected into the oral cavity of NOD.Cg-Prkäcsc,dIl2rgtmlWjl/SzJ (NSG) mice, we observed a small percentage of slow-cycling CD44bright/dye+ long-term labelretaining cells (LRCs) within oral lesions (Fig. 1a, b and Extended Data Fig. 1a-k). Thus, the CD44bright population, which have been shown to have the highest tumour-initiating potential in oral squamous cell carcinomas (OSCCs), displayed cell cycle heterogeneity in vivo21-23. Although the transcriptomes of LRCs (CD44bright dye+) and nonLRCs (dye-) sorted by fluorescence-activated cell sorting (FACS) from orthotopic tongue tumours derived from the OSCC cell line SCC-25...