The Wistar Institute, Philadelphia, Pennsylvania.
University of the Sciences, Philadelphia, Pennsylvania.
Cancer Discov. 2020 Sep;10(9):1282-1295. doi: 10.1158/2159-8290.CD-20-0329. Epub 2020 Jun 4.
Older patients with melanoma (>50 years old) have poorer prognoses and response rates to targeted therapy compared with young patients (<50 years old), which can be driven, in part, by the aged microenvironment. Here, we show that aged dermal fibroblasts increase the secretion of neutral lipids, especially ceramides. When melanoma cells are exposed to the aged fibroblast lipid secretome, or cocultured with aged fibroblasts, they increase the uptake of lipids via the fatty acid transporter FATP2, which is upregulated in melanoma cells in the aged microenvironment and known to play roles in lipid synthesis and accumulation. We show that blocking FATP2 in melanoma cells in an aged microenvironment inhibits their accumulation of lipids and disrupts their mitochondrial metabolism. Inhibiting FATP2 overcomes age-related resistance to BRAF/MEK inhibition in animal models, ablates tumor relapse, and significantly extends survival time in older animals. SIGNIFICANCE: These data show that melanoma cells take up lipids from aged fibroblasts, via FATP2, and use them to resist targeted therapy. The response to targeted therapy is altered in aged individuals because of the influences of the aged microenvironment, and these data suggest FATP2 as a target to overcome resistance...
与年轻患者（<50 岁）相比，老年黑色素瘤（>50 岁）患者的预后和靶向治疗反应率较差，这在一定程度上可以归因于老化的微环境。在这里，我们表明，衰老的真皮成纤维细胞增加了中性脂质的分泌，特别是神经酰胺。当黑色素瘤细胞暴露于衰老的成纤维细胞脂质分泌组或与衰老的成纤维细胞共培养时，它们通过脂肪酸转运蛋白 FATP2 增加脂质的摄取，FATP2 在衰老微环境中的黑色素瘤细胞中上调，已知其在脂质合成和积累中发挥作用。我们表明，在衰老微环境中的黑色素瘤细胞中阻断 FATP2 可抑制其脂质积累并破坏其线粒体代谢。抑制 FATP2 可克服动物模型中与年龄相关的 BRAF/MEK 抑制耐药性，消除肿瘤复发，并显著延长老年动物的生存时间。意义：这些数据表明，黑色素瘤细胞通过 FATP2 从衰老的成纤维细胞中摄取脂质，并利用它们来抵抗靶向治疗。由于老化微环境的影响，个体对靶向治疗的反应发生改变，这些数据表明 FATP2 是克服耐药性的一个靶点。
