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,...

With the goal of increasing the complexity of metallo-supramolecules, two rhombus star-shaped supramolecular architectures, namely, supersnowflakes, were designed and assembled using multiple 2,2':6',2″-terpyridine (tpy) ligands in a stepwise manner. In the design of multicomponent self-assembly, ditopic and tritopic ligands were bridged through Ru(II) with strong coordination to form metal-organic ligands for the subsequent self-assembly with a hexatopic ligand and Zn(II). The combination of Ru(II)-organic ligands with high stability and Zn(II) ions with weak coordination played a key role in the self-assembly of giant heteroleptic supersnowflakes, which encompassed three types of tpy-based organic ligands and two metal ions. With such a stepwise strategy, the self-sorting of individual building blocks was prevented from forming the undesired assemblies, e.g., small macrocycles and coordination polymers. Furthermore, the intra- and intermolecular dynamic exchange study of two supersnowflakes by NMR and mass spectrometry revealed the remarkable stability of these giant supramolecular complexes.

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