Abstract

In order to engage in fast replicative division, a cancer cell must duplicate its genome, synthesise proteins and lipids, and assemble these components to form daughter cells. These activities require increased uptake of nutrients to be used as biosynthetic precursors and an energy source. However, rapid tumour growth surpasses the required blood supply and exposes cancer cells to extreme conditions of metabolic deficit and stress. Therefore, cancer cells undergo many metabolic changes (collectively known as ‘metabolic transformation’) that support their growth and survival. The extent to which metabolism plays a role in tumorigenesis cannot be overstated and drugs that selectively target these processes are likely to at least delay, if not halt tumour progression. Our work utilizes analytical chemistry and system biology approaches to study metabolic transformation. These technologies are not only important for understanding the basic biochemistry of cancer cells but they can inform us on future clinical management of cancer and may lead to new therapeutic approaches to target cancer-specific metabolic pathways.

We investigated cancer cells in which metabolic transformation is mediated by genetic alterations. These include cells which are deficient in one of the two mitochondrial tumour suppressor genes, fumarate hydratase (FH) or succinate dehydrogenase (SDH) or cells that overexpress the glycolytic enzyme pyruvate kinase (PK) M2 isoform (PKM2). We identified several metabolic pathways which are specific and crucial for the survival of FH-deficient cells. These include the heme biosynthesis and degradation pathway as well as mechanisms of alleviating TCA cycle carbon stress.

In addition to high glucose consumption and lactate production, cancer cells are highly dependent on de novo biosynthesis of serine and glycine from glucose. PKM2 , is a highly-regulated PK isoform which catalyses the last step of glycolysis and has recently emerged as a potential regulator of these metabolic phenotypes. However, the mechanisms by which PKM2 coordinates high energy requirements with high anabolic activities, and supports cancer cell proliferation, are still not completely understood. We identified a novel rheostat-like mechanistic relationship between PKM2 activity and serine biosynthesis. We showed that serine can bind to and activate PKM2 and that following serine deprivation, PKM2 activity in cells is reduced. This reduction in PKM2 activity shifts cells to a fuel-efficient mode where more pyruvate is diverted to the mitochondria and more glucose derived carbon is channelled into serine biosynthesis to support cell proliferation.