학술논문
Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
Document Type
Academic Journal
Author
Parida PK; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Marquez-Palencia M; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; 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.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Khandelwal N; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Kim K; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Nair V; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Liu XZ; Department of Biomedicine, University of Bergen, Bergen, Norway.; Vu HS; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Zacharias LG; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Gonzalez-Ericsson PI; Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.; Sanders ME; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Mobley BC; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; McDonald JG; Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Lemoff A; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Peng Y; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Lewis C; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Vale G; Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Halberg N; Department of Biomedicine, University of Bergen, Bergen, Norway.; Arteaga CL; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Hanker AB; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Internal Medicine, 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.; Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Malladi S; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Srinivas.malladi@utsouthwestern.edu.; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA. Srinivas.malladi@utsouthwestern.edu.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101761119 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2662-1347 (Electronic) Linking ISSN: 26621347 NLM ISO Abbreviation: Nat Cancer Subsets: MEDLINE
Subject
Language
English
Abstract
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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)