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Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Published August 24, 2023
Citation Information: J Clin Invest. 2023;133(20):e166644. https://doi.org/10.1172/JCI166644.
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Research Article Oncology Article has an altmetric score of 1

Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma

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Abstract

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.

Authors

Fan Huang, Feiyang Cai, Michael S. Dahabieh, Kshemaka Gunawardena, Ali Talebi, Jonas Dehairs, Farah El-Turk, Jae Yeon Park, Mengqi Li, Christophe Goncalves, Natascha Gagnon, Jie Su, Judith H. LaPierre, Perrine Gaub, Jean-Sébastien Joyal, John J. Mitchell, Johannes V. Swinnen, Wilson H. Miller Jr., Sonia V. del Rincón

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Figure 2

Pex3+/– D4M.3a melanoma cells have altered lipidomes.

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Pex3+/– D4M.3a melanoma cells have altered lipidomes.
(A) Schematic of ...
(A) Schematic of peroxisome-mediated lipid metabolism. VLCFA, very-long-chain fatty acids. (B) Pie charts showing lipid composition (relative abundance of each lipid family in percentage total) in D4M.3a Cas9-Ctrl, Pex3+/– clone 6D, and Pex3+/– clone 9G cells. Concentrations of each lipid family (normalized to mg DNA) are indicated (n = 3). (C) Volcano plots comparing abundance of lipid species in clone 6D versus Cas9-Ctrl (left) and clone 9G versus Cas9-Ctrl (right). Yellow and blue shades highlight respective increased (≥1.5-fold) and decreased (≤1.5-fold) lipid species in Pex3+/– cells relative to Cas9-Ctrl D4M.3a cells. (D) Venn diagrams showing lipid species that were significantly increased (top) or decreased (bottom) in D4M.3a clone 6D and clone 9G cells, compared with Cas9-Ctrl cells. (E) Top: Heatmap showing lipid species that were commonly altered in D4M.3a Pex3+/– (6D and 9G) cells compared with Cas9-Ctrl cells. Bottom: Number of lipid species, categorized by family, enriched in D4M.3a Cas9-Ctrl or Pex3+/– (6D and 9G) cells. PC, phosphatidylcholine; PE, phosphatidylethanolamine; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; TG, triglyceride; PE-O, 1-alkyl,2-acylphosphatidylethanolamine; PC-O, 1-alkyl,2-acylphosphatidylcholine; PC-P, 1-alkenyl,2-acylphosphatidylcholine; PE-P, 1-alkenyl,2-acylphosphatidylethanolamine; DG, diacylglyceride; CE, cholesterol ester. (F) Concentrations of ceramides (left) and hexosylceramides (HexCer, right) detected in D4M.3a Cas9-Ctrl, 6D, and 9G cells (n = 3). Two-way ANOVA. (G–I) Percentage apoptosis (PI+/Annexin V+, PI–/Annexin V+) detected in DMSO- or vemu-treated (G and H) D4M.3a Cas9-Ctrl (left) or Pex3+/– clone 9G (right) or (I) A375M cells. Cells were pretreated with (G and I) C2-ceramide (C2-Cer) at escalated doses or with (H and I) C2-Cer (10 μM) and vorinostat (Vor, 1 μM) 24 hours prior to vemu treatment (n = 4 for H, n = 3 for G, I). Two-way ANOVA. All data represent mean ± SD.

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