Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Abstract

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,...

Urine volatile organic compounds composition in mice bearing breast and melanoma tumors: effect of low-protein diet

“…It may also increase our understanding of the relation between diet and cancer. Our results are in line with the work of Maddocks et al, 44 which show that serine and glycine deprivation inhibits growth of some tumors. Whether this dietary intervention is effective depends on both the oncogenic context and tumor tissue of origin.…”

Targeting Metabolism for Cancer Therapy

“…Certain tumors are dependent on uptake of environmental serine (Jain et al, 2012; Maddocks et al, 2013; Maddocks et al, 2017), and limiting plasma serine availability can be beneficial for patients with these cancers. Removing serine from culture media limits incorporation of one-carbon units into nucleotides and impairs proliferation (Labuschagne et al, 2014).…”

“…Removing serine from culture media limits incorporation of one-carbon units into nucleotides and impairs proliferation (Labuschagne et al, 2014). Additionally, serine deprivation by dietary restriction is sufficient to slow growth of both xenograft (Gravel et al, 2014; Maddocks et al, 2013) and autochthonous cancer models, although efficacy of serine deprivation appears to be influenced by both the oncogenic driver mutation and tissue context (Maddocks et al, 2017). Combining serine restriction with other drugs may also potentiate antitumor responses (Gravel et al, 2014; Maddocks et al, 2013; Maddocks et al, 2017).…”

“…Additionally, serine deprivation by dietary restriction is sufficient to slow growth of both xenograft (Gravel et al, 2014; Maddocks et al, 2013) and autochthonous cancer models, although efficacy of serine deprivation appears to be influenced by both the oncogenic driver mutation and tissue context (Maddocks et al, 2017). Combining serine restriction with other drugs may also potentiate antitumor responses (Gravel et al, 2014; Maddocks et al, 2013; Maddocks et al, 2017). Further understanding the roles of de novo serine synthesis and serine uptake in different tumor contexts can yield important insights into how to target serine metabolism.…”

The big picture: exploring the metabolic cross-talk in cancer

“…However, this effect was only seen in some of the tumour models studied. A notable exception were Kras -driven pancreatic cancers, which can survive serine and glycine starvation by upregulating de novo serine synthesis (Maddocks et al, 2017). This suggests that the impact of restricted diets is determined by the combination of genetic drivers of a given tumour.…”