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

Joanne E Simpson1, Morwenna T Muir1, Martin Lee1

  • 1Cancer Research UK Scotland Centre, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.

Developmental Cell
|December 19, 2023
PubMed

Insights

Autophagy regulates platelet-derived growth factor receptor alpha (PDGFRA) signaling and levels. Autophagy inhibition disrupts PDGFRA trafficking and signaling, impacting PDGFRA-driven gliomagenesis in a genotype-specific manner.

Area of Science:

  • Cell Biology
  • Cancer Biology
  • Molecular Oncology

Background:

  • Autophagy is a fundamental cellular process for degrading damaged components.
  • The role of autophagy in regulating receptor tyrosine kinase signaling during cancer is not well understood.
  • Platelet-derived growth factor receptor alpha (PDGFRA) is implicated in various cancers, including gliomas.

Purpose of the Study:

  • To investigate the role of autophagy in regulating PDGFRA signaling and levels.
  • To elucidate the mechanism by which autophagy influences PDGFRA during tumorigenesis.
  • To determine the impact of autophagy inhibition on PDGFRA-driven gliomagenesis.

Main Methods:

  • Utilized cell-based assays to examine PDGFRA degradation and trafficking.
  • Employed short-term and prolonged autophagy inhibition models.
  • Investigated PDGFRA-driven gliomagenesis in mice with inhibited autophagy, considering Pten status.

Main Results:

  • Autophagy targets PDGFRA for degradation via the p62 cargo receptor.
  • Short-term autophagy inhibition increases PDGFRA levels but impairs signaling due to trafficking defects.
  • Prolonged autophagy inhibition leads to reduced PDGFRA levels, indicating an adaptive response.
  • Autophagy inhibition disrupted PDGFRA-driven gliomagenesis in mice in a Pten-dependent manner.

Conclusions:

  • Autophagy is essential for regulating PDGFRA signaling and levels.
  • Autophagy plays a critical role in driving PDGFRA-mediated tumor formation.
  • The impact of autophagy on gliomagenesis is dependent on the genetic context (Pten status).
Keywords:
PDGFRAPTENRTKautophagycancerendocytosisglioblastomasignaling

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