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

in Developmental cell by Joanne E Simpson, Morwenna T Muir, Martin Lee, Catherine Naughton, Nick Gilbert, Steven M Pollard, Noor Gammoh

TLDR

  • The study found that autophagy plays a crucial role in cancer development by regulating the signaling of a protein called PDGFRA. The study also found that short-term and prolonged autophagy inhibition can affect the levels of PDGFRA and its signaling. The study also found that the impact of autophagy on cancer development depends on the genetic makeup of the cells. The findings suggest that autophagy inhibition could be a potential treatment for cancer.

Abstract

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.

Overview

  • The study investigates the role of autophagy in regulating platelet-derived growth factor receptor alpha (PDGFRA) signaling and levels in cancer development. The study identifies a role for autophagy in targeting PDGFRA for degradation through the activity of the autophagy cargo receptor p62. The study also explores the impact of short-term and prolonged autophagy inhibition on PDGFRA signaling and levels, and its effect on PDGFA-driven gliomagenesis in mice. The hypothesis being tested is that autophagy plays a crucial role in tumorigenesis and its impact on PDGFRA signaling and levels.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically short-term and prolonged autophagy inhibition. The results show that short-term autophagy inhibition leads to elevated levels of PDGFRA but an unexpected defect in PDGFA-mediated signaling due to perturbed receptor trafficking. In contrast, prolonged autophagy inhibition leads to reduced levels of PDGFRA. The study also identifies a genotype-specific role for autophagy during tumorigenesis, as PDGFA-driven gliomagenesis in mice was disrupted when autophagy was inhibited in a manner dependent on Pten status.

Implications and Future Directions

  • The study's findings highlight the importance of autophagy in regulating PDGFRA signaling and levels during cancer development. The study also identifies a mechanism by which cells require autophagy to drive tumor formation. The study's findings have significant implications for the field of research and clinical practice, as they suggest that autophagy inhibition could be a potential therapeutic strategy for cancer treatment. Future research directions could explore the role of autophagy in other types of cancer and investigate the potential of autophagy inhibitors as a therapeutic approach for cancer treatment.
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