We recently heard from Dr Anna Smith and Dr Julia Whitehall as part of our WCMR Science Seminar Series. The title of their talk was “Investigating the effect of age-related mitochondrial dysfunction on intestinal tumour formation and progression: a model in the making – one size does not fit all”. Read on to find out more.
Within our cells the mitochondria are central to energy production and metabolism. During ageing, an accumulation of damage to the mitochondria in our cells leads to an energy production defect, which affects the functioning and health of our tissues. The intestine is one such tissue that has been investigated in our lab. In humans, an accumulation of damage is seen to occur in the stem cells responsible for the regeneration and cellular balance of the intestine. Notably the origin of colorectal cancer is known to initiate from these intestinal stem cells and colorectal tumours have been previously reported to contain defective mitochondria. Consequently, our research group are investigating the physiological effects of an age accumulation of damage to the mitochondria in the intestinal stem cells.
To directly investigate these age-related effects during the development of colorectal cancer, we have generated a mouse model which accumulates damage to their mitochondria with age and displays characteristics of human ageing and an energy defect. When these mice develop intestinal tumours, they have an increased tumour burden, shorter life expectancy and upregulate specific metabolic pathways known to aid cell growth and defence. As such, we have generated a live 3D cancer cell model which recapitulates the growth and tumour features seen in the mouse intestine. We show that tumours, through the upregulation of these metabolic pathways due to an age-associated accumulation of damage to their mitochondria, are resilient to a shortage of specific nutrients in the environment. We go onto demonstrate that human patient colorectal adenocarcinomas with defective mitochondria have this metabolic reprogramming that may enable an advantageous profile for cancer cell growth.
We are now using a range of strategies to develop clinically relevant mouse and human 3D cancer models with defective mitochondria. These models will allow us to better understand the effect of mitochondrial dysfunction in later stages of malignancy, and to test the therapeutic potential of inhibiting those compensatory favourable metabolic pathways as novel strategies for cancer treatment.