CD36-Mediated Lipid Metabolism Promotes Metastasis

Tumor-initiating cells (TIC) exhibit the ability to proliferate, differentiate, and give rise to new tumors; however, it is not known whether TICs, or a subset of TICs, also exhibit the ability to promote metastasis. To ascertain whether TICs harbor a subpopulation of metastasis-initiating cells, Pascual and colleagues orthotopically injected immunodeficient mice with oral squamous cell carcinoma (OSCC) cell lines labeled with a lipophilic dye that tracks cell division and isolated dye⁺ long-term label-retaining cells (LRC) that were highly positive for CD44, a marker of cells with high tumor-initiating potential, from oral lesions. Expression profiling revealed that genes associated with chromosomal instability and cell cycle were upregulated in CD44^bright/dye⁻ cells, while genes associated with metastasis and lipid metabolism, particularly the receptor CD36, were upregulated in CD44^bright LRCs. Overexpression of CD36, which enhances the uptake of fatty acids, significantly increased lymph node metastasis of OSCC cell lines with low metastatic potential; conversely, depletion of CD36 almost completely ablated metastasis of highly metastatic OSCC cell lines and significantly reduced metastasis of breast cancer and melanoma cell lines. Consistent with these findings, CD36⁺ OSCC cells, but not CD36⁻ OSCC cells, formed lymph node metastases, and treatment with anti-CD36 neutralizing antibodies inhibited OSCC metastasis initation and induced significant regression of established OSCC metastases, but did not affect primary tumor growth, in immunocompromised mice, and inhibited metastasis in immunocompetent mice without toxicity. Further, administration of a high-fat diet or the dietary fatty acid palmitic acid enhanced the development of CD36⁺ metastases, suggesting that CD36⁺ cells promote metastasis by internalizing fatty acids and activating lipid β-oxidation. Expression of CD36 or the CD36⁺-associated gene signature significantly correlated with poor survival in patients with lung, bladder, or breast cancer. Together, these results identify a metastasis-initiating subpopulation of TICs that drives metastasis in a lipid metabolism–dependent manner and suggest that targeting this subpopulation may be a potential antimetastasis therapy.

Pascual G, Avgustinova A, Mejetta S, Martín M, Castellanos A, Attolini CS, et al. Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 2016 Dec 7 [Epub ahead of print].