SummaryA functional genomics study revealed that the activity of acetyl-CoA synthetase 2 (ACSS2) contributes to cancer cell growth under low-oxygen and lipid-depleted conditions. Comparative metabolomics and lipidomics demonstrated that acetate is used as a nutritional source by cancer cells in an ACSS2-dependent manner, and supplied a significant fraction of the carbon within the fatty acid and phospholipid pools. ACSS2 expression is upregulated under metabolically stressed conditions and ACSS2 silencing reduced the growth of tumor xenografts. ACSS2 exhibits copy-number gain in human breast tumors, and ACSS2 expression correlates with disease progression. These results signify a critical role for acetate consumption in the production of lipid biomass within the harsh tumor microenvironment.

Previous work has shown that some cancer cells are highly dependent on serine/glycine uptake for proliferation. Although serine and glycine can be interconverted and either might be used for nucleotide synthesis and one-carbon metabolism, we show that exogenous glycine cannot replace serine to support cancer cell proliferation. Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. We conclude that nucleotide synthesis and cancer cell proliferation are supported by serine--rather than glycine--consumption.

Maddocks, O. D. K. et al. (2017) Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature, 544(7650), pp. 372-376.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/140432/ AbstractThe non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis 2,3,4 , many others rely on exogenous serine for optimal growth 5,6,7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7,8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Krasdriven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.To assess the effect of dietary serine and glycine (SG) restriction in autochthonous tumour models, we used genetically engineered mouse models (GEMMs) of lymphoma (Eμ-Myc) and intestinal tumours (defective Apc). Eμ-Myc mice develop pre-neoplastic lesions within 28-42 days after birth 9 , and adenoma initiation is evident days after birth in Apc Min/+ mice 10 . Accordingly, Apc Min/+ mice carried high tumour numbers at 80 days, which subsequently increased in size but not number (Extended Data Fig. 1a). Transferring mice from normal chow diet to experimental diets 60-80 days after birth showed that an SG-free diet significantly extended survival in these models carrying pre-malignant lesions (Fig. 1a, b), with a slightly lower tumour burden in Apc Min/+ mice on the SG-free diet at clinical end point (Extended Data Fig. 1a). The diet reproducibly decreased serum SG from around 150 μM to 65 μM (Fig. 1c-e), while showing minimal or inconsistent impact on other amino acids, glucose and lactate (Fig. 1c, d and Extended Data Figs 1b, 2a, b), These results were further validated using an inducible intestinal tumour model (Lgr5-creER;Apc fl/fl ); transferring mice to the SG-free diet a week after induction. Again, the experimental diet caused a significant increase in survival compared to control diet (containing purified amino acids) or normal chow (containing whole protein as a source of amino acids) (Fig. 1f). (c, control, n = 14; control,...