| Literature DB >> 33073241 |
Anna Lm Smith1,2, Julia C Whitehall1,2, Carla Bradshaw1,2, David Gay3,4, Fiona Robertson1,5, Alasdair P Blain1,5, Gavin Hudson1,2, Angela Pyle1,2, David Houghton1,5, Matthew Hunt1,5, James N Sampson1,5, Craig Stamp1,2, Grace Mallett5, Shoba Amarnath5, Jack Leslie6, Fiona Oakley6, Laura Wilson7, Angela Baker1,5, Oliver M Russell1,5, Riem Johnson1,5, Claire A Richardson5, Bhavana Gupta1,2, Iain McCallum5, Stuart Ac McDonald8, Seamus Kelly5, John C Mathers9, Rakesh Heer7, Robert W Taylor1,5, Neil D Perkins2, Doug M Turnbull1,5, Owen J Sansom3,4, Laura C Greaves1,2.
Abstract
Oxidative phosphorylation (OXPHOS) defects caused by somatic mitochondrial DNA (mtDNA) mutations increase with age in human colorectal epithelium and are prevalent in colorectal tumours, but whether they actively contribute to tumorigenesis remains unknown. Here we demonstrate that mtDNA mutations causing OXPHOS defects are enriched during the human adenoma/carcinoma sequence, suggesting they may confer a metabolic advantage. To test this we deleted the tumour suppressor Apc in OXPHOS deficient intestinal stem cells in mice. The resulting tumours were larger than in control mice due to accelerated cell proliferation and reduced apoptosis. We show that both normal crypts and tumours undergo metabolic remodelling in response to OXPHOS deficiency by upregulating the de novo serine synthesis pathway (SSP). Moreover, normal human colonic crypts upregulate the SSP in response to OXPHOS deficiency prior to tumorigenesis. Our data show that age-associated OXPHOS deficiency causes metabolic remodelling that can functionally contribute to accelerated intestinal cancer development.Entities:
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Year: 2020 PMID： 33073241 PMCID： PMC7116185 DOI： 10.1038/s43018-020-00112-5
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347