In a recent presentation as part of our WCMR science seminar series, we heard from Dr Julia Whitehall and Dr Anna Smith about their research into the effects of age-related alterations in mitochondria within intestinal stem cells. Read on to find out more.
Mitochondria are central to energy production and metabolism within our cells. During ageing, our mitochondria accumulate alterations leading to an energy production defect that affects the functioning and health of our tissues. The intestine is one such tissue that has been investigated in our lab. The intestinal stem cells, responsible for the regeneration and cellular balance of the intestine, have previously been shown to accumulate alterations with age and be the initial cell in the development of colorectal cancer. Alongside this, colorectal tumours have been reported to contain altered mitochondria. Consequently, our research group are investigating the physiological effects of an age-related accumulation of alterations within 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 alterations within their mitochondria with age and displays characteristics of human ageing and an energy defect. When these mice are induced to develop intestinal tumours, they have an increased tumour burden, shorter life expectancy and an upregulation of 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 through the upregulation of these metabolic pathways due to an age-associated accumulation of alterations within their mitochondria, tumours are resilient to a shortage of specific nutrients in the environment. We go on to demonstrate that human patient colorectal adenocarcinomas with altered mitochondria also have this metabolic reprogramming that may enable an advantageous profile for cancer cell growth.
We are now using a range of strategies to develop pre-clinical in vitro models and screening tools that may help our understanding of the underlying mechanisms and uncover metabolic vulnerabilities that may be used in colorectal cancer treatment and prognosis.
The team would like to acknowledge support from the Bowel Disease Research Fund, the JGW Patterson Foundation and Wellcome.