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Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
Parida, Pravat Kumar; Marquez-Palencia, Mauricio; Ghosh, Suvranil; Khandelwal, Nitin; Kim, Kangsan; Nair, Vidhya; Liu, Xiao-Zheng; Vu, Hieu S; Zacharias, Lauren G; Gonzalez-Ericsson, Paula I; Sanders, Melinda E; Mobley, Bret C; McDonald, Jeffrey G; Lemoff, Andrew; Peng, Yan; Lewis, Cheryl; Vale, Gonçalo; Halberg, Nils; Arteaga, Carlos L; Hanker, Ariella B; DeBerardinis, Ralph J; Malladi, Srinivas.
Afiliación
  • Parida PK; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Marquez-Palencia M; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Ghosh S; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Khandelwal N; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Kim K; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Nair V; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Liu XZ; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Vu HS; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Zacharias LG; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Gonzalez-Ericsson PI; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Sanders ME; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Mobley BC; Department of Biomedicine, University of Bergen, Bergen, Norway.
  • McDonald JG; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Lemoff A; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Peng Y; Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Lewis C; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Vale G; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Halberg N; Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Arteaga CL; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Hanker AB; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • DeBerardinis RJ; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • Malladi S; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Cancer ; 4(6): 893-907, 2023 06.
Article en En | MEDLINE | ID: mdl-37248394
Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Neoplasias de la Mama Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Encefálicas / Neoplasias de la Mama Tipo de estudio: Prognostic_studies Límite: Female / Humans Idioma: En Revista: Nat Cancer Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido