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Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer

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Abstract

Mitochondrial DNA (mtDNA) encodes for only a fraction of the proteins that are encoded within the nucleus, and therefore has typically been regarded as a lesser player in cancer biology and metastasis. Accumulating evidence, however, supports an increased role for mtDNA impacting tumor progression and metastatic susceptibility. Unfortunately, due to this delay, there is a dearth of data defining the relative contributions of specific mtDNA polymorphisms (SNP), which leads to an inability to effectively use these polymorphisms to guide and enhance therapeutic strategies and diagnosis. In addition, evidence also suggests that differences in mtDNA impact not only the cancer cells but also the cells within the surrounding tumor microenvironment, suggesting a broad encompassing role for mtDNA polymorphisms in regulating the disease progression. mtDNA may have profound implications in the regulation of cancer biology and metastasis. However, there are still great lengths to go to understand fully its contributions. Thus, herein, we discuss the recent advances in our understanding of mtDNA in cancer and metastasis, providing a framework for future functional validation and discovery.

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Abbreviations

bp:

Base pair

CAF:

Cancer-associated fibroblasts

cfDNA:

Cell-free DNA

CTC:

Circulating tumor cell

ROS:

Reactive oxygen species

ETC:

Electron transport chain

EWAS:

Epigenome-wide association study

EMT:

Epithelial-mesenchymal transition

ECAR:

Extracellular acidification ratio

GWAS:

Genome-wide association study

mtDNA:

Mitochondrial DNA

MNX:

Mitochondrial-nuclear exchange mouse

NGS:

Next-generation sequencing

nDNA:

Nuclear DNA

nt:

Nucleotide

OCR:

oxygen consumption ratio

SNP:

Single-nucleotide polymorphism

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Acknowledgements

We are deeply indebted to all members of the Welch lab, Isidore Rigoutsos and Kent Hunter for insights and inspiration. We apologize to any authors whose work was omitted due to article guidelines.

Funding

Work done in the authors’ labs was funded by Susan G. Komen for the Cure (SAC110037) and the National Foundation for Cancer Research. Additional funding support was provided by the U.S. Army Medical Research Defense Command Breast Cancer Research Program under Award No. W81XWH1810450, (TCB); National Cancer Institute P30-CA168524 (DRW), and National Institutes of Health GM103418 (TCB and DRW). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense.

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  1. Department of Cancer Biology, The Kansas University Medical Center, 3901 Rainbow Blvd, Kansas City, KS, 66160, USA

    Thomas C. Beadnell, Adam D. Scheid, Carolyn J. Vivian & Danny R. Welch

  2. The University of Kansas Cancer Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA

    Danny R. Welch

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Beadnell, T.C., Scheid, A.D., Vivian, C.J. et al. Roles of the mitochondrial genetics in cancer metastasis: not to be ignored any longer. Cancer Metastasis Rev 37, 615–632 (2018). https://doi.org/10.1007/s10555-018-9772-7

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