Abstract
Rewired metabolism of glutamine in cancer has been well documented, but less is known about other amino acids such as histidine. Here, we use Drosophila cancer models to show that decreasing the concentration of histidine in the diet strongly inhibits the growth of mutant clones induced by loss of Nerfin‐1 or gain of Notch activity. In contrast, changes in dietary histidine have much less effect on the growth of wildtype neural stem cells and Prospero neural tumours. The reliance of tumours on dietary histidine and also on histidine decarboxylase (Hdc) depends upon their growth requirement for Myc. We demonstrate that Myc overexpression in nerfin‐1 tumours is sufficient to switch their mode of growth from histidine/Hdc sensitive to resistant. This study suggests that perturbations in histidine metabolism selectively target neural tumours that grow via a dedifferentiation process involving large cell size increases driven by Myc.
Highlights
One hallmark of tumours is that they display a high demand for certain nutrients, at least in part reflecting their fast growth and proliferation (Cantor & Sabatini, 2012)
With respect to amino acid metabolism, c-MYC induces fibroblasts to become dependent upon glutamine for survival (Yuneva et al, 2007); cysteine deprivation triggers programmed necrosis in von Hippel–Lindau (VHL)-deficient clearcell renal cancer cells but not in VHL-restored counterparts (Tang et al, 2016); and mutation of p53 influences how tumour growth is affected by serine metabolism (Maddocks et al, 2013)
In nerfin-1 mutant clones, neurons switch off the expression of differentiation genes in favour of stem cell markers, resulting in tumour-like lineages which exhibit unlimited proliferative potential, that fail to differentiate and are metastatic when transplanted into naive adult hosts (Froldi et al, 2015 and Fig 1A)
Summary
One hallmark of tumours is that they display a high demand for certain nutrients, at least in part reflecting their fast growth and proliferation (Cantor & Sabatini, 2012). Representative pictures showing that larval pros clonal growth was not significantly altered by dietary histidine reduction (25% his) compared to CDD (after 6 days), quantified in (T) (n = 19, 13).
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