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

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.