Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the...

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Autores: Mahmood, Mahnoor, Minwei Liu, Eric, Shergold, Amy L., Tolla, Elisabetta, Tait-Mulder, Jacqueline, Huerta-Uribe, Alejandro, Shokry, Engy, Young, Alex L., Lilla, Sergio, Kim, Minsoo, Park, Tricia, Boscenco, Sonia, Manchón, Javier L., Rodríguez-Antona, Cristina, Walters, Rowan C., Springett, Roger J., Blaza, James N., Mitchell, Louise, Blyth, Karen, Zanivan, Sara, Sumpton, David, Roberts, Edward W., Reznik, Ed, Gammage, Payam A.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/389180
Acceso en línea:http://hdl.handle.net/10261/389180
Access Level:acceso abierto
Palabra clave:Cancer
Cancer genetics
Cancer immunotherapy
Cancer metabolism
Cancer microenvironment
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spelling Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanomaMahmood, MahnoorMinwei Liu, EricShergold, Amy L.Tolla, ElisabettaTait-Mulder, JacquelineHuerta-Uribe, AlejandroShokry, EngyYoung, Alex L.Lilla, SergioKim, MinsooPark, TriciaBoscenco, SoniaManchón, Javier L.Rodríguez-Antona, CristinaWalters, Rowan C.Springett, Roger J.Blaza, James N.Mitchell, LouiseBlyth, KarenZanivan, SaraSumpton, DavidRoberts, Edward W.Reznik, EdGammage, Payam A.CancerCancer geneticsCancer immunotherapyCancer metabolismCancer microenvironmentThe mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.This work was supported by CRUK Glasgow Centre (A18076), CRUK SI Advanced Technology Facilities (A17196). S.Z. was supported by Stand Up to Cancer campaign for CRUK SI Core Funding (A29800). P.A.G was supported by CRUK SI Core Funding (A31287 and A_BICR_1920_Gammage), European Research Council (ERC) Starting Grant (via UKRI: EP/X035581/1) and NIH (R37CA276200). E.R. was supported by Department of Defense Kidney Cancer Research Program (no. HT9425-23-1-0995), NIH R37 CA276200 and the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center. This work was supported by NIH/NCI Cancer Center Support Grant (P30 CA008748).Peer reviewedSpringer NatureCancer Research UKEuropean Research CouncilNational Institutes of Health (US)Alan and Sandra Gerry Metastasis and Tumor Ecosystems CenterNational Cancer Institute (US)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/389180reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s43018-023-00721-whttps://doi.org/10.1038/s43018-023-00721-wSíinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3891802026-05-22T06:33:51Z
dc.title.none.fl_str_mv Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
title Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
spellingShingle Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
Mahmood, Mahnoor
Cancer
Cancer genetics
Cancer immunotherapy
Cancer metabolism
Cancer microenvironment
title_short Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
title_full Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
title_fullStr Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
title_full_unstemmed Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
title_sort Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma
dc.creator.none.fl_str_mv Mahmood, Mahnoor
Minwei Liu, Eric
Shergold, Amy L.
Tolla, Elisabetta
Tait-Mulder, Jacqueline
Huerta-Uribe, Alejandro
Shokry, Engy
Young, Alex L.
Lilla, Sergio
Kim, Minsoo
Park, Tricia
Boscenco, Sonia
Manchón, Javier L.
Rodríguez-Antona, Cristina
Walters, Rowan C.
Springett, Roger J.
Blaza, James N.
Mitchell, Louise
Blyth, Karen
Zanivan, Sara
Sumpton, David
Roberts, Edward W.
Reznik, Ed
Gammage, Payam A.
author Mahmood, Mahnoor
author_facet Mahmood, Mahnoor
Minwei Liu, Eric
Shergold, Amy L.
Tolla, Elisabetta
Tait-Mulder, Jacqueline
Huerta-Uribe, Alejandro
Shokry, Engy
Young, Alex L.
Lilla, Sergio
Kim, Minsoo
Park, Tricia
Boscenco, Sonia
Manchón, Javier L.
Rodríguez-Antona, Cristina
Walters, Rowan C.
Springett, Roger J.
Blaza, James N.
Mitchell, Louise
Blyth, Karen
Zanivan, Sara
Sumpton, David
Roberts, Edward W.
Reznik, Ed
Gammage, Payam A.
author_role author
author2 Minwei Liu, Eric
Shergold, Amy L.
Tolla, Elisabetta
Tait-Mulder, Jacqueline
Huerta-Uribe, Alejandro
Shokry, Engy
Young, Alex L.
Lilla, Sergio
Kim, Minsoo
Park, Tricia
Boscenco, Sonia
Manchón, Javier L.
Rodríguez-Antona, Cristina
Walters, Rowan C.
Springett, Roger J.
Blaza, James N.
Mitchell, Louise
Blyth, Karen
Zanivan, Sara
Sumpton, David
Roberts, Edward W.
Reznik, Ed
Gammage, Payam A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Cancer Research UK
European Research Council
National Institutes of Health (US)
Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center
National Cancer Institute (US)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Cancer
Cancer genetics
Cancer immunotherapy
Cancer metabolism
Cancer microenvironment
topic Cancer
Cancer genetics
Cancer immunotherapy
Cancer metabolism
Cancer microenvironment
description The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/389180
url http://hdl.handle.net/10261/389180
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s43018-023-00721-w
https://doi.org/10.1038/s43018-023-00721-w
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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