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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 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.

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Change history

  • 13 December 2016

    The received date was corrected in the HTML.

  • 04 January 2017

    The Competing Interests statement and the Acknowledgements funding information were updated.

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Acknowledgements

Research in the laboratory of S.A.B. for this project is supported by the European Research Council (ERC), the Government of Cataluña (SGR grant), the Fundación Botín and Banco Santander, through Santander Universities, and Worldwide Cancer Research. We would like to thank the Beug Stiftung Foundation for their support. S.M. was supported by a La Caixa International PhD fellowship. A.A. was supported by an EU Cofound postdoctoral fellowship. L.D.C. was supported by the Spanish ‘Ministerio de Educación y Ciencia’ (SAF2013-48926-P) and the European Commission’s 7th Framework Program 4DCellFate grant number 277899. We thank the Vall D´Hebron Research Institute Tumor Biobank for their assistance with the human samples. We also thank R. Wong for the Ln-7 cell line and J. Zuber for the PMSCV-Luc2-PGKneo-Ires GFP vector. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). We thank V. Raker for manuscript editing.

Author information

Affiliations

  1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain

    • Gloria Pascual
    • , Alexandra Avgustinova
    • , Mercè Martín
    • , Andrés Castellanos
    • , Camille Stephan-Otto Attolini
    • , Antoni Berenguer
    • , Neus Prats
    •  & Salvador Aznar Benitah
  2. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain

    • Stefania Mejetta
    •  & Luciano Di Croce
  3. IMIM, Department of Dermatology, Hospital del Mar, 08003 Barcelona

    • Agustí Toll
  4. Vall D´Hebron Hospital, Barcelona, Department of Oral and Maxillofacial Surgery, Universitat Autònoma de Barcelona, Barcelona 08035 Spain

    • Juan Antonio Hueto
    •  & Coro Bescós
  5. Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain

    • Luciano Di Croce
    •  & Salvador Aznar Benitah
  6. Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain

    • Luciano Di Croce

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Contributions

G.P. and S.A.B. designed all experiments. G.P. performed all experiments with the help of M.M. for the histological characterization of the lipotoxicity and A.C. for the analysis of the gene expression data. A.A. established the patient-derived cells and the oral cancer orthotopic method. C.S.-O.A. and A.B. performed statistical analyses. J.A.H., C.B. and A.T. provided the tumours from patients. S.M. established the dye protocol to detect LRCs. N.P. performed the histopathology analysis of the mice. L.D.C. analysed expression data. G.P. and S.A.B. wrote the manuscript.

Competing interests

The Institute for Research in Biomedicine in Barcelona has filed a provisional patent application that covers the application of inhibition of the fatty acid receptor CD3 by any method as an antimetastatic therapy against oral squamous cell carcinoma (European patent application number EP 2016/073208). Authors S.A.B., G.P., A.C. and M.M. are listed as inventors.

Corresponding author

Correspondence to Salvador Aznar Benitah.

Reviewer Information Nature thanks A. Harris and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20791

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