Abstract

The control of metabolism is a fundamental requirement for all life, with perturbations of metabolic homeostasis underpinning numerous pathologies. While altered metabolism in tumour cells was described almost a century ago, recent work is beginning to reveal how these changes help to support the growth and survival of cancer cells in stressful microenvironments. These metabolic alterations help to promote tumorigenesis, but may also provide targetable vulnerabilities in cancer compared to normal cells that could be exploited for therapy. One challenge facing cancer cells is fluctuating nutrient availability and recent work has highlighted the importance of serine uptake to support one-carbon metabolism via the THF cycle. We have found that the tumour suppressor p53 can help to support the adaptation of cancer cells to serine starvation by facilitating the switch to the de novo serine synthesis pathway (SSP). The activation of p53 in response to serine depletion leads to a transient cell cycle arrest, allowing the cells to channel metabolites into glutathione synthesis and survive increased oxidative stress. Interestingly, many transformed cells are highly dependent on the uptake of exogenous serine and dietary depletion of serine in vivo reduces cancer growth without impacting general health. Surprisingly, despite being interconvertible with serine, glycine cannot substitute for serine in supporting tumour cell growth and our analyses indicate that this is due to a depletion of one-carbon pools in glycine-fed cells, supporting previous data showing excess glycine can be detrimental to tumour growth. De novo serine synthesis involves the diversion of glycolytic intermediates into the SSP, resulting in a greater dependence on OXPHOS to provide energy. As predicted, we have also shown a synergy between serine depletion and inhibitors of OXPHOS and we are testing some of these combinations in experimental tumor therapy. Other metabolic pathways, for example the control of lipid synthesis, are also beginning to reveal new therapeutic targets as well as the potential of repurposing drugs designed to treat other metabolic diseases for cancer therapy.

Funded by CR-UK, ERC and MRC.