Targeting metastasis-initiating cells through the fatty acid receptor CD36

• Published in: Nature (London) 2017-01, Vol.541 (7635), p.41-45
• Main Authors: Pascual, Gloria, Avgustinova, Alexandra, Mejetta, Stefania, Martín, Mercè, Castellanos, Andrés, Attolini, Camille Stephan-Otto, Berenguer, Antoni, Prats, Neus, Toll, Agustí, Hueto, Juan Antonio, Bescós, Coro, Di Croce, Luciano, Benitah, Salvador Aznar
• Format: Article
• Language: English
• Subjects: 631/67/1665; 631/67/322; Animals; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; Antibodies, Neutralizing - therapeutic use; Cancer cells; Cancer metastasis; CD36 Antigens - antagonists & inhibitors; CD36 Antigens - genetics; CD36 Antigens - immunology; CD36 Antigens - metabolism; Cell Proliferation; Cells; Diet, High-Fat - adverse effects; Disease Models, Animal; Fatty acids; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; Humanities and Social Sciences; Humans; Hyaluronan Receptors - metabolism; Lipid metabolism; Lipid Metabolism - genetics; Lipids; Lymphatic Metastasis - genetics; Lymphatic Metastasis - pathology; Male; Melanoma; Metabolism; Metastasis; Mice; Mouth Neoplasms - diagnosis; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; multidisciplinary; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; Neoplasm Metastasis - prevention & control; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oral cancer; Palmitic Acid - administration & dosage; Palmitic Acid - metabolism; Palmitic Acid - pharmacology; Penetrance; Physiological aspects; Prognosis; Science; Transcriptome; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature20791

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 CD44 bright 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. Human oral carcinoma cells expressing high levels of the fatty acid receptor CD36 initiate metastasis in mouse models, and metastasis is increased by palmitic acid or a fatty diet and decreased by blockade of CD36. Metastasis-initiating cells in oral carcinoma The ability to identify cells with metastatic potential is of clinical importance for the development of anti-metastatic treatment. Salvador Aznar Benitah and colleagues have identified high metastatic potential in a population of cells expressing high levels of the fatty acid receptor CD36 in human oral carcinoma samples. The cells initiate metastasis in mouse models. Metastasis is increased by palmitic acid or a fatty diet, and decreased by CD36 blockade.