Histidine is selectively required for the growth of Myc-dependent dedifferentiation tumours in the Drosophila CNS

EMBO J. 2019 Apr 1;38(7):e99895. doi: 10.15252/embj.201899895. Epub 2019 Feb 25.

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.

Keywords: Drosophila; dedifferentiation; histidine; metabolism; neuroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Dedifferentiation*
  • Central Nervous System Neoplasms / genetics
  • Central Nervous System Neoplasms / metabolism
  • Central Nervous System Neoplasms / pathology*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / metabolism*
  • Female
  • Histidine / administration & dosage*
  • Histidine Decarboxylase / genetics
  • Histidine Decarboxylase / metabolism
  • Male
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Myc protein, Drosophila
  • Transcription Factors
  • nerfin-1 protein, Drosophila
  • Histidine
  • Histidine Decarboxylase