The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma

Irene Lasheras-Otero, Iker Feliu, Alberto Maillo, Haritz Moreno, Marta Redondo-Muñoz, Paula Aldaz, Ana Bocanegra, Ana Olias-Arjona, Fernando Lecanda, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Ignacio M Larrayoz, David Gomez-Cabrero, Claudia Wellbrock, Silvestre Vicent, Imanol Arozarena

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Circulating tumor cells (CTCs) are the key link between a primary tumor and distant metastases, but once in the bloodstream loss of adhesion induces cell death. To identify mechanisms relevant for melanoma CTC survival we performed RNAseq and discovered that detached melanoma cells and isolated melanoma CTCs rewire lipid metabolism by up-regulating fatty acid transport and fatty acid beta-oxidation (FAO) related genes. In melanoma patients high expression of fatty acid transporters and FAO enzymes significantly correlates with reduced progression free and overall survival. Amongst the highest expressed regulators in melanoma CTCs were the carnitine-transferases CROT and CRAT, which control the shuttle of peroxisome derived medium-chain fatty acids (MCFAs) towards mitochondria to fuel mitochondrial FAO. Knockdown of CROT or CRAT and short-term treatment with peroxisomal or mitochondrial FAO inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. CROT and CRAT depletion could be rescued by MCFA supplementation, indicating that the peroxisomal supply of fatty acids is crucial for the survival of non-adherent melanoma cells. Our study identifies targeting the fatty acid based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity to challenge melanoma progression. Moreover, the discovery of the anti-metastatic activity of the FDA-approved drug ranolazine carries translational potential.
Original languageEnglish (US)
JournalThe Journal of investigative dermatology
DOIs
StatePublished - Sep 1 2022

Bibliographical note

KAUST Repository Item: Exported on 2022-09-14
Acknowledgements: We thank Guadalupe Gutierrez and Beatriz Rodriguez from the Navarrabiomed Biobank for their help with the processing and staining of tumor samples. This work was funded by the Instituto de Salud Carlos III-FEDER through [PI16-01911] and [PI19/00645] to I.A. I.A. and I.M.L. acknowledge support through Miguel Servet II fellowships [CPII20/00011] and [CPII20/00029]. The Health Department of the Government of Navarra, Spain funded work through [Ref: GºNa 71/17]. S.V. is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación [PID2020-116344-RB-100] and by Foundation AECC [PROYE20029VICE]. ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma [ref: Beca_GEM]. FL was funded by Cancer Research Thematic Network of the Instituto de Salud Carlos III [RTICC RD12/0036/0066], SAF2015-71606R, RTI2018-094507-B-100 financed by MCIN/ AEI /10.13039/501100011033/ and by FEDER. F.L. was also funded by “la Caixa” Foundation, Caja Navarra Foundation and the Foundation AECC. P.A is recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III [CD21/00137].

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Dermatology

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