title: Mitochondrial DNA plasticity is an essential inducer of tumorigenesis.
abstract: Although mitochondrial DNA has been implicated in diseases such as cancer, its role remains to be defined. Using three models of tumorigenesis, namely glioblastoma multiforme, multiple myeloma and osteosarcoma, we show that mitochondrial DNA plays defining roles at early and late tumour progression. Specifically, tumour cells partially or completely depleted of mitochondrial DNA either restored their mitochondrial DNA content or actively recruited mitochondrial DNA, which affected the rate of tumorigenesis. Nevertheless, non-depleted tumour cells modulated mitochondrial DNA copy number at early and late progression in a mitochondrial DNA genotype-specific manner. In glioblastoma multiforme and osteosarcoma, this was coupled with loss and gain of mitochondrial DNA variants. Changes in mitochondrial DNA genotype affected tumour morphology and gene expression patterns at early and late progression. Importantly, this identified a subset of genes that are essential to early progression. Consequently, mitochondrial DNA and commonly expressed early tumour-specific genes provide novel targets against tumorigenesis.
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: W T Y
authors.initials: WT
authors.lastname: Lee
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Cain
authors.affiliation: Myeloma Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University , Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Cuddihy
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Dickinson
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Yeung
authors.affiliation: Department of Pathology, Monash Health , Clayton, Victoria, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia; Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: T G
authors.initials: TG
authors.lastname: Johns
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Randwick, New South Wales, Australia; Department of Thoracic Medicine, St Vincent's Hospital, Darlinghurst, New South Wales, Australia.
authors.forename: D N
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: Myeloma Research Group, Division of Blood Cancers, Australian Centre for Blood Diseases, Monash University, Victoria, Australia; Malignant Haematology & Stem Cell Transplantation, Alfred Health, 55 Commercial Road, Melbourne, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Spencer
authors.affiliation: Centre for Genetic Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
authors.forename: J C
authors.initials: JC
authors.lastname: St John