CELULAS CIRCULANTES DE TUMORES COMO DIANAS PARA LA PREVENCION DEL DESARROLLO DE MELANOMA METASTASICO
PI19/00645
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Nombre agencia financiadora Instituto de Salud Carlos III
Acrónimo agencia financiadora ISCIII
Programa Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I
Subprograma Subprograma Estatal de Generación de Conocimiento
Convocatoria Proyectos de investigación en salud
Año convocatoria 2019
Unidad de gestión Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 (ISCIII)
Centro beneficiario FUNDACION INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA
Centro realización INSTITUTO DE INVESTIGACION SANITARIA DE NAVARRA (IdISNA)
Identificador persistente https://doi.org/10.13039/501100004587
Publicaciones
Resultados totales (Incluyendo duplicados): 1
Encontrada(s) 1 página(s)
Encontrada(s) 1 página(s)
The regulators of peroxisomal acyl-carnitine shuttle CROT and CRAT promote metastasis in melanoma
Academica-e. Repositorio Institucional de la Universidad Pública de Navarra
- Lasheras Otero, Irene
- Feliu, Iker
- Maíllo Ruiz de Infante, Alberto
- Moreno, Haritz
- Redondo Muñoz, Marta
- Aldaz Donamaría, Paula
- Bocanegra Gondán, Ana Isabel
- Olías Arjona, Ana
- Lecanda, Fernando
- Fernández Irigoyen, Joaquín
- Santamaría Martínez, Enrique
- Larráyoz, Ignacio M.
- Gómez-Cabrero, David
- Wellbrock, Claudia
- Vicent, Silvestre
- Arozarena Martinicorena, Imanol
Circulating tumor cells are the key link between a primary tumor and distant metastases, but once in the
bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating
tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated
melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA betaoxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation
enzymes significantly correlates with reduced progression-free and overall survival. Among the highest
expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs
toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or
carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase
and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that
the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies
targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity
to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug
Administration‒approved drug ranolazine carries translational potential., This work was funded by the Instituto de Salud Carlos III-FEDER through PI16-01911 and PI19/00645 to IA. IA and IML acknowledge support through Miguel Servet II fellowships (CPII20/00011 and CPII20/00029). The Health Department of the Government of Navarra, Spain funded work through reference GºNa 71/17. SV is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (PID2020-116344-RB-100) and by Foundation Spanish Association Against Cancer (PROYE20029VICE). ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma (reference Beca_GEM). FL was funded by the 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. FL was also funded by the la Caixa Foundation, Caja Navarra Foundation, and the Foundation AECC. PA is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III (CD21/00137).
bloodstream, loss of adhesion induces cell death. To identify the mechanisms relevant for melanoma circulating
tumor cell survival, we performed RNA sequencing and discovered that detached melanoma cells and isolated
melanoma circulating tumor cells rewire lipid metabolism by upregulating fatty acid (FA) transport and FA betaoxidation‒related genes. In patients with melanoma, high expression of FA transporters and FA beta-oxidation
enzymes significantly correlates with reduced progression-free and overall survival. Among the highest
expressed regulators in melanoma circulating tumor cells were the carnitine transferases carnitine O-octanoyltransferase and carnitine acetyltransferase, which control the shuttle of peroxisome-derived medium-chain FAs
toward mitochondria to fuel mitochondrial FA beta-oxidation. Knockdown of carnitine O-octanoyltransferase or
carnitine acetyltransferase and short-term treatment with peroxisomal or mitochondrial FA beta-oxidation inhibitors thioridazine or ranolazine suppressed melanoma metastasis in mice. Carnitine O-octanoyltransferase
and carnitine acetyltransferase depletion could be rescued by medium-chain FA supplementation, indicating that
the peroxisomal supply of FAs is crucial for the survival of nonadherent melanoma cells. Our study identifies
targeting the FA-based cross-talk between peroxisomes and mitochondria as a potential therapeutic opportunity
to challenge melanoma progression. Moreover, the discovery of the antimetastatic activity of the Food and Drug
Administration‒approved drug ranolazine carries translational potential., This work was funded by the Instituto de Salud Carlos III-FEDER through PI16-01911 and PI19/00645 to IA. IA and IML acknowledge support through Miguel Servet II fellowships (CPII20/00011 and CPII20/00029). The Health Department of the Government of Navarra, Spain funded work through reference GºNa 71/17. SV is funded by FEDER/Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (PID2020-116344-RB-100) and by Foundation Spanish Association Against Cancer (PROYE20029VICE). ILO is funded through a Navarrabiomed PhD studentship and the Grupo Español Multidisciplinar de Melanoma (reference Beca_GEM). FL was funded by the 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. FL was also funded by the la Caixa Foundation, Caja Navarra Foundation, and the Foundation AECC. PA is a recipient of a Sara Borrell postdoctoral fellowship from the Instituto de Salud Carlos III (CD21/00137).