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Lookup NU author(s): Anna Smith, Dr Julia Whitehall, Carla Bradshaw, Dr Fiona Robertson, Dr Alasdair Blain, Professor Gavin Hudson, Dr Angela Pyle, Dr Dave Houghton, Matthew Hunt, Dr James Sampson, Dr Craig Stamp, Grace Mallett, Dr Shoba AmarnathORCiD, Dr Jack LeslieORCiD, Professor Fiona OakleyORCiD, Laura WilsonORCiD, Angela Baker, Dr Oliver Russell, Riem Johnson, Dr Claire Richardson, Dr Iain McCallum, Seamus Kelly, Professor John Mathers, Professor Rakesh Heer, Professor Robert Taylor, Professor Neil PerkinsORCiD, Emeritus Professor Doug Turnbull, Professor Laura GreavesORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature, 2020.
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Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumors, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mitochondrial DNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting that they may confer a metabolic advantage. To test this, we deleted the tumor suppressor Apc in OXPHOS-deficient intestinal stem cells in mice. The resulting tumors were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumors undergo metabolic remodeling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway. Moreover, normal human colonic crypts upregulate the serine synthesis pathway in response to OXPHOS deficiency before tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodeling that can functionally contribute to accelerated intestinal cancer development.
Author(s): Smith ALM, Whitehall JC, Bradshaw C, Gay D, Robertson F, Blain AP, Hudson G, Pyle A, Houghton D, Hunt M, Sampson JN, Stamp C, Mallett G, Amarnath S, Leslie J, Oakley F, Wilson L, Baker A, Russell OM, Johnson R, Richardson CA, Gupta B, McCallum I, McDonald SAC, Kelly S, Mathers JC, Heer R, Taylor RW, Perkins ND, Turnbull DM, Sansom OJ, Greaves LC
Publication type: Article
Publication status: Published
Journal: Nature Cancer
Year: 2020
Volume: 1
Pages: 976-989
Print publication date: 01/10/2020
Online publication date: 21/09/2020
Acceptance date: 05/08/2020
Date deposited: 13/11/2020
ISSN (electronic): 2662-1347
Publisher: Nature
URL: https://doi.org/10.1038/s43018-020-00112-5
DOI: 10.1038/s43018-020-00112-5
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