title: Targeting metastasis-initiating cells through the fatty acid receptor CD36.
abstract: 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 CD44brightcells 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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Pascual
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Avgustinova
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mejetta
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Martín
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Castellanos
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Camille Stephan-Otto
authors.initials: CS
authors.lastname: Attolini
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Antoni
authors.initials: A
authors.lastname: Berenguer
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
authors.forename: Neus
authors.initials: N
authors.lastname: Prats
authors.affiliation: IMIM, Department of Dermatology, Hospital del Mar, 08003 Barcelona.
authors.forename: Agustí
authors.initials: A
authors.lastname: Toll
authors.affiliation: Vall D´Hebron Hospital, Barcelona, Department of Oral and Maxillofacial Surgery, Universitat Autònoma de Barcelona, Barcelona 08035 Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Hueto
authors.affiliation: Vall D´Hebron Hospital, Barcelona, Department of Oral and Maxillofacial Surgery, Universitat Autònoma de Barcelona, Barcelona 08035 Spain.
authors.forename: Coro
authors.initials: C
authors.lastname: Bescós
authors.affiliation: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain.
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.|Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.
authors.forename: Salvador Aznar
authors.initials: SA
authors.lastname: Benitah
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D018955:CD36 Antigens / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008207:Lymphatic Metastasis / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D009062:Mouth Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D019308:Palmitic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D019683:Penetrance; D011379:Prognosis; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D057134:Antibodies, Neutralizing; D018955:CD36 Antigens; D018960:Hyaluronan Receptors; D019308:Palmitic Acid