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,...

Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53 allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53 are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.

Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose, whose excessive intake causes intestinal barrier deterioration and endotoxemia. However, how fructose triggers these alterations and their role in hepatosteatosis and NASH pathogenesis remain unknown. By preventing fructose and endoplasmic reticulum stressdependent barrier deterioration and subsequent endotoxemia using a chemical chaperon, activation of mucosal-regenerative gp130 signaling, administration of the YAP-induced matricellular protein CCN1 or expression of anti-microbial Reg3β peptide, we show that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1 phosphate (F1P) and cytosolic acetyl-CoA. TLR engagement triggers TNF production by liver macrophages to induce lipogenic enzymes that convert F1P and acetyl-CoA to FA in mouse and human hepatocytes.