Determining the functional role of mitochondrial DNA mutations in colorectal cancer Pathogenesis

Alterations in mitochondrial metabolism are major hallmarks of both ageing cells and cancer. Age is thebiggest risk factor for the development of a significant number of cancer types and this therefore raisesthe question of whether there is a link between age-related mitochondrial dysfunction and theadvantageous changes in mitochondrial metabolism prevalent in cancer cells. 

A common underlyingfeature of both ageing and cancer cells is the presence of somatic mutations of the mitochondrialgenome (mtDNA). MtDNA mutations are particularly enriched in colorectal cancers (Gorelick et al.(2021) Nat Metab 3: 558-570), and we have previously shown that individual normal human colonic cryptstem cells also accumulate somatic mtDNA point mutations with age (Greaves et al. (2010) ExpGerontol 45: 573-579). This shows that somatic mtDNA mutations and altered metabolic pathways arepresent in colonic crypts prior to malignant transformation, suggesting that mtDNA mutations may eitherincrease the risk of malignant transformation, promote tumour progression, or are selectively propagatedduring tumour development. 

To investigate this we generated a mouse model in which we inducedtumours specifically in intestinal stem cells with and without mtDNA mutation-induced mitochondrialdysfunction. We found that the mice with mitochondrial dysfunction had similar numbers of tumours tocontrols but they were growing significantly faster resulting in a shortened lifespan (Smith et al. (2020)Nature Cancer 1: 976-989). Multi-omics analysis revealed the underlying mechanism to be anupregulation of the de novo serine synthesis pathway and mitochondrial one-carbon metabolism inresponse to mitochondrial dysfunction. 

These anabolic pathways are important regulators of cellularbiomass production and, excitingly, may represent metabolic vulnerabilities for therapeutic exploitation inhuman colorectal cancer. In this presentation I will discuss some of the new technological approacheswe are taking to investigate this further and present new preliminary data.