Mitochondrial DNA is a major source of driver mutations in cancer

Kim, Min‐Soo; Mahmood, Mahnoor; Reznik, Ed; Gammage, Payam A.

doi:10.1016/j.trecan.2022.08.001

Cited by 43 publications

(39 citation statements)

References 90 publications

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“…Several studies confirm that tumours can develop from single clones which acquire a set of mutations driving overgrowth [ 52 , 53 ]. These mutations are of diverse origins: they can be inherited in the autosomal or mitochondrial DNA, induced by chemical carcinogens or environmental factors, or modulated by the individual’s microbiome [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ] ( Figure 1 ). Tumours, while growing, increase by volume and thus the contact area with the wild-type host tissues also increases.…”

Section: Cell Competition In Primary and Secondary Cancer Growthmentioning

confidence: 99%

Stemming Tumoral Growth: A Matter of Grotesque Organogenesis

Merino

García‐Sanz

2023

Cells

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The earliest metazoans probably evolved from single-celled organisms which found the colonial system to be a beneficial organization. Over the course of their evolution, these primary colonial organisms increased in size, and division of labour among the cells became a remarkable feature, leading to a higher level of organization: the biological organs. Primitive metazoans were the first organisms in evolution to show organ-type structures, which set the grounds for complex organs to evolve. Throughout evolution, and concomitant with organogenesis, is the appearance of tissue-specific stem cells. Tissue-specific stem cells gave rise to multicellular living systems with distinct organs which perform specific physiological functions. This setting is a constructive role of evolution; however, rebel cells can take over the molecular mechanisms for other purposes: nowadays we know that cancer stem cells, which generate aberrant organ-like structures, are at the top of a hierarchy. Furthermore, cancer stem cells are the root of metastasis, therapy resistance, and relapse. At present, most therapeutic drugs are unable to target cancer stem cells and therefore, treatment becomes a challenging issue. We expect that future research will uncover the mechanistic “forces” driving organ growth, paving the way to the implementation of new strategies to impair human tumorigenesis.

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Section: Cell Competition In Primary and Secondary Cancer Growthmentioning

confidence: 99%

Stemming Tumoral Growth: A Matter of Grotesque Organogenesis

Merino

García‐Sanz

2023

Cells

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“…It has been known for several decades that >50% of cancers bear somatic mutations of mtDNA 5 . The impact of mtDNA mutations in the germline, the most common cause of inherited metabolic disease in humans 6 , is well-established.…”

Section: Mainmentioning

confidence: 99%

“…The impact of mtDNA mutations in the germline, the most common cause of inherited metabolic disease in humans 6 , is well-established. However, the biological and clinical relevance of mtDNA mutations in cancer remains contentious 5 . Recent efforts have yielded evidence for recurrence and selection of mtDNA mutations in .…”

Section: Mainmentioning

confidence: 99%

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Mahmood

Liu

Shergold

et al. 2023

Preprint

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The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology, we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti-tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

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“…Transferring tumor mitochondria to a normal cell by anastomoses or extracellular vesicles would transmit mutations in mitochondria DNA that have been considered oncogenic [171], and also has the potential to make the target cell neoplastic by reprograming its metabolism [172], with the concomitant production of oncometabolites, which are metabolites that deregulate gene expression if present at an increased concentration [158,159]. Given their size, oncometabolites can also be transferred by gap junctional channels.…”

Section: What Components Need To Be Transferred To Induce a Neoplasti...mentioning

confidence: 99%

Adopted neoplastic cells and the consequences of their existence

Lazebnik¹

2023

Oncotarget

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A view that guides the bulk of cancer research and oncology posits that each neoplastic cell in a tumor is a genetic offspring of another neoplastic cell. Yet, analyzing tumors from transplant patients has revealed that some normal migratory cells adopt the phenotype of neoplastic cells without acquiring their genome, thus becoming what I suggest to call adopted neoplastic cells. This commentary reviews the evidence for the existence of adopted neoplastic cells, outlines the consequences of their presence, and discusses what kind of cells can be adopted, how, and why.

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Mitochondrial DNA is a major source of driver mutations in cancer

Cited by 43 publications

References 90 publications

Stemming Tumoral Growth: A Matter of Grotesque Organogenesis

Stemming Tumoral Growth: A Matter of Grotesque Organogenesis

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

Adopted neoplastic cells and the consequences of their existence

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