Fatty acid metabolism regulates cell survival in specific niches

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Two studies recently published in Nature demonstrate the crucial role played by fatty acid import and oxidation in the physiological or pathological maintenance of given cell types in specific locations of the organism. The first one [1▪▪] describes the lipid-dependence of a specific pool of memory T cells, the tissue-resident memory T (TRM) cells, for their long-term survival. TRM cells permanently reside in epithelia located at the interface between the host and the environment where they can be recruited upon infection to induce fast and efficient recall responses [2,3]. The maintenance of this T-cell subset in barrier tissues may implicate specific cytokines but the mechanisms driving the longevity of TRM cells in this particular location remained obscure. The laboratory of Thomas Kupper followed the gene expression profile of TRM cells as they settle down in their final location and found that they acquired a stable and unique signature 25 days after the infection that generated them. The redundant fatty acid-binding protein (FABP) 4 and FABP5 and the CD36 scavenger receptor were among the top upregulated genes and this correlated with the increased ability of TRM cells to take up fatty acids. It was then discovered that the absence of both FABP4 and FABP5 prevents TRM cells from using and metabolizing fatty acids, leading to their faster disappearance from tissues. Consequently, mice lacking FABP4 and FABP5 were found to be unable to efficiently fight viral infections. This work provides solid evidence that TRM cells have adapted their metabolism to survive in barrier tissues such as the skin that are lipid-rich but relatively poor in other nutrients. The ability to thrive in the presence of lipids represents therefore an important adaptive physiological mechanism for certain cell types to reside in specific locations but it can be perverted by malignant cells to establish themselves in new environments during metastatization, as exemplified by the findings reported in a second Nature paper [4▪▪]. This study characterized a slow-cycling population in oral squamous cell carcinomas (OSCCs) that express high levels of CD36, the same scavenger receptor identified by the Kupper's study in TRM cells. CD36 can bind a variety of lipoproteins and lipids and coordinates fat uptake and utilization in cells [5,6]. The authors of this second study found that the slow-cycling CD36-expressing cells within the primary tumor are metastasis-initiating cells and that CD36 expression is required for the resulting metastases to use fatty acids for their growth. Without CD36, the metastatic cells accumulated unmetabolized lipids and died by apoptosis. However, dietary fat boosted the growth of CD36+ metastasis-initiating cells. Anti-CD36 neutralizing antibodies efficiently blocked metastatization from OSCCs in mouse models. Of clinical relevance, expression of CD36 in various human cancers correlated with poor disease-free survival. This work is of particular interest because it highlights the detrimental role played by fatty acids in cancer progression and provides the scientific basis for a therapeutical approach targeting CD36 for blocking the metastatic process.
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