Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.

Humans Female Breast Neoplasms / drug therapy Dynamins / metabolism Mitochondria / metabolism Cell Line, Tumor Brain Neoplasms / drug therapy

Journal

Nature cancer
ISSN: 2662-1347
Titre abrégé: Nat Cancer
Pays: England
ID NLM: 101761119

Informations de publication

Date de publication:
06 2023
Historique:
received: 14 09 2022
accepted: 17 04 2023
medline: 28 6 2023
pubmed: 30 5 2023
entrez: 29 5 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s43018-023-00563-6 PMID: 37248394
pubmed: 37248394
doi: 10.1038/s43018-023-00563-6
pii: 10.1038/s43018-023-00563-6
doi:

Substances chimiques

Dynamins EC 3.6.5.5

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

893-907

Subventions

Organisme : NCI NIH HHS
ID : R35 CA220449
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA142543
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Auteurs

Pravat Kumar 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.

Mauricio 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.

Suvranil 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.

Nitin Khandelwal (N)

Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Kangsan 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.

Vidhya 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.

Xiao-Zheng Liu (XZ)

Department of Biomedicine, University of Bergen, Bergen, Norway.

Hieu S Vu (HS)

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Lauren G Zacharias (LG)

Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Paula I Gonzalez-Ericsson (PI)

Breast Cancer Research Program, Vanderbilt University Medical Center, Nashville, TN, USA.
ORCID: 0000-0002-6292-6963

Melinda E Sanders (ME)

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Bret C Mobley (BC)

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Jeffrey G McDonald (JG)

Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
ORCID: 0000-0003-1570-4142

Andrew Lemoff (A)

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Yan 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.

Cheryl 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.

Gonçalo Vale (G)

Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
ORCID: 0000-0003-1104-0289

Nils Halberg (N)

Department of Biomedicine, University of Bergen, Bergen, Norway.
ORCID: 0000-0002-2943-3147

Carlos L Arteaga (CL)

Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
ORCID: 0000-0003-0870-9586

Ariella B 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.
ORCID: 0000-0002-8655-8341

Ralph J 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.
ORCID: 0000-0002-2705-7432

Srinivas 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.
ORCID: 0000-0002-0829-2365

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Limiting mitochondrial plasticity by targeting...
questionsmedicales.fr › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Maladies du sein › Tumeurs du sein › Limiting mitochondrial plasticity by targeting...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Dynamines › Limiting mitochondrial plasticity by targeting...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Mitochondries › Limiting mitochondrial plasticity by targeting...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Limiting mitochondrial plasticity by targeting...
questionsmedicales.fr › Maladies du système nerveux › Tumeurs du système nerveux › Tumeurs du système nerveux central › Tumeurs du cerveau › Limiting mitochondrial plasticity by targeting...