Targeting metastasis-initiating cells through the fatty acid receptor CD36

Gloria Pascual; Alexandra Avgustinova; Stefania Mejetta; Mercè Martín; Andrés Castellanos; Camille Stephan-Otto Attolini; Antoni Berenguer; Neus Prats; Agustí Toll; Juan Antonio Hueto; Coro Bescós; Luciano Di Croce; Salvador Aznar Benitah

doi:10.1038/nature20791

Targeting metastasis-initiating cells through the fatty acid receptor CD36

Nature. 2017 Jan 5;541(7635):41-45. doi: 10.1038/nature20791. Epub 2016 Dec 7.

Authors

Affiliations

¹ Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain.
² Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Dr. Aiguader 88, 08003 Barcelona, Spain.
³ IMIM, Department of Dermatology, Hospital del Mar, 08003 Barcelona.
⁴ Vall D´Hebron Hospital, Barcelona, Department of Oral and Maxillofacial Surgery, Universitat Autònoma de Barcelona, Barcelona 08035 Spain.
⁵ Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.
⁶ Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain.

PMID: 27974793
DOI: 10.1038/nature20791

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 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Neutralizing / immunology
Antibodies, Neutralizing / pharmacology*
Antibodies, Neutralizing / therapeutic use
CD36 Antigens / antagonists & inhibitors*
CD36 Antigens / genetics
CD36 Antigens / immunology
CD36 Antigens / metabolism
Cell Proliferation
Diet, High-Fat / adverse effects
Disease Models, Animal
Female
Gene Expression Regulation, Neoplastic
Humans
Hyaluronan Receptors / metabolism
Lipid Metabolism / genetics
Lymphatic Metastasis / genetics
Lymphatic Metastasis / pathology
Male
Mice
Mouth Neoplasms / diagnosis
Mouth Neoplasms / drug therapy
Mouth Neoplasms / metabolism
Mouth Neoplasms / pathology*
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*
Palmitic Acid / administration & dosage
Palmitic Acid / metabolism
Palmitic Acid / pharmacology
Penetrance
Prognosis
Transcriptome
Xenograft Model Antitumor Assays

Substances

Antibodies, Neutralizing
CD36 Antigens
Hyaluronan Receptors
Palmitic Acid

Grants and funding

13-1064/AICR_/Worldwide Cancer Research/United Kingdom