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An Arf/Rab cascade controls the growth and invasiveness of glioblastoma

Gopinath Kulasekaran1, Mathilde Chaineau1, Valerio Emilio Crescenzo Piscopo1

  • 1Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.

The Journal of Cell Biology
|January 14, 2021
PubMed

Insights

Loss of endosomal GTPase Rab35 function accelerates glioblastoma growth and reduces survival. The Arf5/Rab35 pathway regulates cell migration and tumor invasiveness, offering new therapeutic targets for brain cancer.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Glioblastoma is the most aggressive primary brain tumor with poor prognosis.
  • Endosomal trafficking pathways are crucial for cancer cell functions.
  • The role of specific GTPases like Rab35 in glioblastoma remains incompletely understood.

Purpose of the Study:

  • To investigate the function of the endosomal GTPase Rab35 in glioblastoma.
  • To elucidate the molecular mechanisms regulating Rab35 activity in brain tumor initiating cells (BTICs).
  • To identify novel therapeutic targets for glioblastoma treatment.

Main Methods:

  • Utilized human brain tumor initiating cells (BTICs) and mouse models of glioblastoma.
  • Performed knockdown studies of Rab35 and Arf5.
  • Employed RNA sequencing (RNAseq) to analyze tumor gene expression.
  • Investigated protein-protein interactions and enzyme kinetics (GEF activity).

Main Results:

  • Loss of Rab35 function in BTICs significantly increased glioblastoma growth and decreased animal survival.
  • The GTPase Arf5 was identified to allosterically enhance the guanine nucleotide exchange factor (GEF) activity of DENND1 towards Rab35.
  • Knockdown of Rab35 or Arf5 promoted cell migration, invasiveness, and self-renewal, and enhanced tumor growth and invasiveness in vivo.
  • Disruption of the Arf5/Rab35 axis led to epidermal growth factor receptor (EGFR) activation and upregulation of the transcription factor SPOCD1.

Conclusions:

  • The Arf5-DENND1-Rab35 cascade is a critical regulator of glioblastoma progression.
  • This pathway influences key cancer hallmarks including cell migration, invasion, and self-renewal.
  • Targeting this endosomal trafficking pathway presents a potential therapeutic strategy for glioblastoma.

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