Around 60% of all human tumours carry mutations in their mitochondrial DNA, yet these genetic changes have been largely ignored in cancer research. This project aims to change that by creating the first accurate laboratory models of colorectal cancer that carry specific, cancer-relevant mitochondrial DNA mutations. The problem is that existing mouse models rely on random, continuous mutations that do not mimic real human disease. Without faithful models, researchers cannot answer fundamental questions about how mitochondrial DNA mutations influence whether a tumour grows, spreads, or responds to treatment. The lead researcher’s own recent work showed that certain mitochondrial mutations in colorectal cancer can dramatically extend lifespan in mice—the first robust evidence that these mutations have real clinical consequences. If successful, this project will deliver three advances: new mouse models with controllable mutation levels, models bearing mutations identical to those found in human patients, and entirely new tools for editing mitochondrial DNA that go far beyond current capabilities. This is primarily fundamental science—it will answer basic questions about how mitochondrial genetics modify cancer behaviour. But the tools created here could eventually help researchers identify which patients might benefit from treatments targeting mitochondrial function, or predict how aggressive a cancer will be based on its mitochondrial DNA profile.
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Mutations of mtDNA are present in ~60% of all tumours and have long been overlooked in cancer biology. Recent groundbreaking work from my lab has identified mtDNA mutations as a major phenotype-modifier across all cancers, and mtDNA mutations in colorectal cancer were linked to major extensions in lifespan, the first robust evidence for the clinical impact of mtDNA mutations in cancer. However, the mechanistic details of this effect, alongside fundamental questions of the role mtDNA mutations play in cancer initiation and progression remain unaddressed, with a lack of experimental mtDNA model systems available to investigate this further. To date, the field has relied on mouse models that undergo random and continuous mutagenesis of mtDNA, which do not recapitulate the disease state. Applying my expertise at the intersection of mitochondrial and cancer biology with my highly specialist, proven track record in mtDNA genome engineering, I propose creation of models and methods to advance understanding of mitochondrial genetics in cancer, addressing the present discovery-limiting technical shortfall. Taking colorectal cancer as an initial paradigm, I will: i) use advanced mtDNA manipulation tools of my own invention to create new state-of-the-art mouse models of colorectal cancer with manipulable levels of a cancer-relevant mtDNA mutation (WP1); ii) apply and modify recently developed mtDNA mutagenesis methods to create new state-of-the-art models of colorectal cancer bearing mtDNA mutations analogous to those I identified in human disease (WP2); iii) develop methods to revolutionise genetic manipulation of mtDNA, permitting creation of any mtDNA variant - well beyond the present state-of-the-art (WP3). Through this proposal, I will answer fundamental questions of how colorectal cancer is modified by mtDNA mutational state (Aim 1) while creating broadly applicable mtDNA tools and models to power further research into cancer far beyond present technical limits (Aim 2).
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