2. Academic Validation
  3. Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2

Changes in Aged Fibroblast Lipid Metabolism Induce Age-Dependent Melanoma Cell Resistance to Targeted Therapy via the Fatty Acid Transporter FATP2

  • Cancer Discov. 2020 Sep;10(9):1282-1295. doi: 10.1158/2159-8290.CD-20-0329.
Gretchen M Alicea 1 2 3 4,  Vito W Rebecca 1,  Aaron R Goldman 1,  Mitchell E Fane 1 3 4,  Stephen M Douglass 1 3 4,  Reeti Behera 1,  Marie R Webster 1 5,  Curtis H Kugel 3rd 1,  Brett L Ecker 1 6,  M Cecilia Caino 7,  Andrew V Kossenkov 1,  Hsin-Yao Tang 1,  Dennie T Frederick 8,  Keith T Flaherty 8,  Xiaowei Xu 6,  Qin Liu 1,  Dmitry I Gabrilovich 1,  Meenhard Herlyn 1,  Ian A Blair 6,  Zachary T Schug 1,  David W Speicher 1,  Ashani T Weeraratna 9 3 4
Affiliations

Affiliations

  • 1 The Wistar Institute, Philadelphia, Pennsylvania.
  • 2 University of the Sciences, Philadelphia, Pennsylvania.
  • 3 Johns Hopkins School of Public Health, Baltimore, Maryland.
  • 4 Johns Hopkins School of Medicine, Baltimore, Maryland.
  • 5 Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
  • 6 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7 University of Colorado, Denver, Colorado.
  • 8 Massachussetts General Hospital, Boston, Massachusetts.
  • 9 The Wistar Institute, Philadelphia, Pennsylvania. [email protected].
PMID: 32499221 DOI: 10.1158/2159-8290.CD-20-0329
Abstract

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.See related commentary by Montal and White, p. 1255.This article is highlighted in the In This Issue feature, p. 1241.

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