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SUMMARY:Mitochondrial DNA mutations in cancer – passive bystanders or ac
 tive participants? - Professor Laura Greaves\, University of Newcastle
DTSTART:20241113T150000Z
DTEND:20241113T160000Z
UID:TALK222742@talks.cam.ac.uk
CONTACT:Lisa Arnold
DESCRIPTION:Abstract: Alterations in mitochondrial metabolism are major ha
 llmarks of both ageing cells and cancer. Age is the biggest risk factor fo
 r the development of a significant number of cancer types and this therefo
 re raises the question of whether there is a link between age-related mito
 chondrial dysfunction and the advantageous changes in mitochondrial metabo
 lism prevalent in cancer cells. A common underlying feature of both ageing
  and cancer cells is the presence of somatic mutations of the mitochondria
 l genome (mtDNA). MtDNA mutations are particularly enriched in colorectal 
 cancers (Gorelick et al. (2021) Nat Metab 3: 558-570)\, and we have previo
 usly shown that individual normal human colonic crypt stem cells also accu
 mulate somatic mtDNA point mutations with age (Greaves et al. (2010)  Exp 
 Gerontol 45: 573-579). This shows that somatic mtDNA mutations and altered
  metabolic pathways are present in colonic crypts prior to malignant trans
 formation\, suggesting that mtDNA mutations may either increase the risk o
 f malignant transformation\, promote tumour progression\, or are selective
 ly propagated during tumour development.  To investigate this we generated
  a mouse model in which we induced tumours specifically in intestinal stem
  cells with and without mtDNA mutation-induced mitochondrial dysfunction. 
 We found that the mice with mitochondrial dysfunction had similar numbers 
 of tumours to controls but they were growing significantly faster resultin
 g in a shortened lifespan (Smith et al. (2020) Nature Cancer 1: 976-989). 
 Multi-omics analysis revealed the underlying mechanism to be an upregulati
 on of the de novo serine synthesis pathway and mitochondrial one-carbon me
 tabolism in response to mitochondrial dysfunction. These anabolic pathways
  are important regulators of cellular biomass production and\, excitingly\
 , may represent metabolic vulnerabilities for therapeutic exploitation in 
 human colorectal cancer. In the seminar I will discuss the new directions 
 we are taking with this work and the new technologies we are applying to f
 urther advance our knowledge in this area.
LOCATION:MRC MBU\, Level 7 Lecture Theatre\, The Keith Peters Building\, C
 B2 0XY
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