2. Academic Validation
  3. The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma

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

  • J Invest Dermatol. 2022 Sep 1;S0022-202X(22)01890-5. doi: 10.1016/j.jid.2022.08.038.
Irene Lasheras-Otero 1,  Iker Feliu 2,  Alberto Maillo 3,  Haritz Moreno 2,  Marta Redondo-Muñoz 1,  Paula Aldaz 1,  Ana Bocanegra 4,  Ana Olias-Arjona 1,  Fernando Lecanda 5,  Joaquin Fernandez-Irigoyen 6,  Enrique Santamaria 7,  Ignacio M Larrayoz 8,  David Gomez-Cabrero 9,  Claudia Wellbrock 10,  Silvestre Vicent 11,  Imanol Arozarena 12
Affiliations

Affiliations

  • 1 Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain.
  • 2 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Program in Solid Tumors, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain.
  • 3 Translational Bioinformatics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain.
  • 4 Oncoimmunology Group, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain.
  • 5 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Program in Solid Tumors, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; School of Medicine, Department of Pathology, Anatomy and Physiology, University of Navarra, 31008 Pamplona, Spain.
  • 6 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Proteomics Platform, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain.
  • 7 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Clinical Neuroproteomics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain.
  • 8 Biomarkers and Molecular Signaling Group, Center for Biomedical Research of La Rioja (CIBIR), Foundation Rioja Salud, 26006 Logroño, La Rioja, Spain; Unidad Predepartamental de Enfermería, Universidad de La Rioja (UR), 26006 Logroño, La Rioja, Spain.
  • 9 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Translational Bioinformatics Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain; Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
  • 10 Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain.
  • 11 IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain; Program in Solid Tumors, Centre for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 12 Cancer Signaling Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), 31008 Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, 31008 Pamplona, Spain. Electronic address: [email protected].
PMID: 36058299 DOI: 10.1016/j.jid.2022.08.038
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.

Keywords

CRAT; CROT; anoikis; fatty acid oxidation; melanoma; metastasis.

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