Autophagy supports PDGFRA-dependent brain tumour development by modulating oncogenic signalling

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Autophagy is a highly conserved catabolic process which sequesters intracellular substrates for lysosomal degradation. Whilst autophagy-related proteins have been shown to regulate the signalling and trafficking of some receptor tyrosine kinases, the relevance of this during cancer development is unclear. Here, we uncover a novel role for autophagy in regulating PDGFRA signalling and levels. We find that PDGFRA can be targeted to autophagic degradation through the activity of the autophagy cargo receptor, p62. As a result, short term autophagy inhibition leads to elevated intracellular levels of PDGFRA but an unexpected defect in PDGFA-mediated downstream signalling due to perturbed trafficking of the receptor. Defective PDGFRA signalling led to a reduction in receptor levels during prolonged autophagy inhibition suggesting that cells adapt to autophagy inhibition by downregulating receptor expression. Importantly, PDGFA-driven gliomagenesis in mice was disrupted when autophagy was inhibited. Activation of PI3K/AKT signalling through Pten mutation overrides the need for autophagy during tumour development upon PDGFRA activation highlighting a genotype-specific role for autophagy during tumourigenesis. In summary, our data provide a novel mechanism by which cells require autophagy for optimal oncogenic signalling that drives tumour formation.
Original languageEnglish
JournalDevelopmental Cell
Early online date18 Dec 2023
Publication statusE-pub ahead of print - 18 Dec 2023

Keywords / Materials (for Non-textual outputs)

  • Autophagy
  • cancer
  • endocytosis
  • glioblastoma
  • PTEN
  • RTK
  • signalling


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