Autophagy supports PDGFRA-dependent brain tumor development by enhancing oncogenic signaling

Autophagy is a conserved cellular degradation process. While autophagy-related proteins were shown to influence the signaling and trafficking of some Receptor Tyrosine Kinases, the relevance of this during Cancer development is unclear. Here, we identify a role for Autophagy in regulating platelet-derived growth factor receptor alpha (PDGFRA) signaling and levels. We find that PDGFRA can be targeted for autophagic degradation through the activity of the Autophagy cargo receptor p62. As a result, short-term Autophagy inhibition leads to elevated levels of PDGFRA but an unexpected defect in PDGFA-mediated signaling due to perturbed receptor trafficking. Defective PDGFRA signaling led to its reduced levels during prolonged Autophagy inhibition, suggesting a mechanism of adaptation. Importantly, PDGFA-driven gliomagenesis in mice was disrupted when Autophagy was inhibited in a manner dependent on PTEN status, thus highlighting a genotype-specific role for Autophagy during tumorigenesis. In summary, our data provide a mechanism by which cells require Autophagy to drive tumor formation.