Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.

Autor: Kim M; Tri-Institutional PhD Program in Computational Biology & Medicine, Weill Cornell Medicine, New York City, NY, USA.; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Gorelick AN; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Vàzquez-García I; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Williams MJ; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Salehi S; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Shi H; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Weiner AC; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Ceglia N; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Funnell T; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Park T; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Boscenco S; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., O'Flanagan CH; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Jiang H; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Grewal D; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Tang C; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Rusk N; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Gammage PA; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.; CRUK Beatson Institute, Glasgow, UK., McPherson A; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA., Aparicio S; Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada., Shah SP; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. shahs3@mskcc.org., Reznik E; Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, NY, USA. reznike@mskcc.org.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 May; Vol. 56 (5), pp. 889-899. Date of Electronic Publication: 2024 May 13.
DOI: 10.1038/s41588-024-01724-8
Abstrakt: The extent of cell-to-cell variation in tumor mitochondrial DNA (mtDNA) copy number and genotype, and the phenotypic and evolutionary consequences of such variation, are poorly characterized. Here we use amplification-free single-cell whole-genome sequencing (Direct Library Prep (DLP+)) to simultaneously assay mtDNA copy number and nuclear DNA (nuDNA) in 72,275 single cells derived from immortalized cell lines, patient-derived xenografts and primary human tumors. Cells typically contained thousands of mtDNA copies, but variation in mtDNA copy number was extensive and strongly associated with cell size. Pervasive whole-genome doubling events in nuDNA associated with stoichiometrically balanced adaptations in mtDNA copy number, implying that mtDNA-to-nuDNA ratio, rather than mtDNA copy number itself, mediated downstream phenotypes. Finally, multimodal analysis of DLP+ and single-cell RNA sequencing identified both somatic loss-of-function and germline noncoding variants in mtDNA linked to heteroplasmy-dependent changes in mtDNA copy number and mitochondrial transcription, revealing phenotypic adaptations to disrupted nuclear/mitochondrial balance.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: