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A kinase-deficient NTRK2 splice variant predominates in glioma and amplifies several oncogenic signaling pathways

Siobhan S Pattwell1, Sonali Arora1, Patrick J Cimino1,2

  • 1Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA, 98109, USA.

Nature Communications
|June 14, 2020
PubMed

Insights

A novel truncated Tropomyosin receptor kinase B (TrkB.T1) splice variant drives glioma growth by activating PI3K signaling pathways. This finding underscores the importance of studying splice variants in neuro-oncology.

Area of Science:

  • Neuro-oncology
  • Molecular biology
  • Cancer research

Background:

  • Aberrant splicing patterns are implicated in oncogenesis.
  • Novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) are found in gliomas.
  • Tropomyosin receptor kinase B (TrkB), encoded by NTRK2, plays key roles in neuronal functions and has complex splicing.

Purpose of the Study:

  • To investigate the role of a specific NTRK2 splice variant, TrkB.T1, in human glioma.
  • To understand the molecular mechanisms by which TrkB.T1 influences glioma progression.

Main Methods:

  • In vivo glioma models.
  • In vitro cell signaling assays.
  • Next-generation sequencing (NGS) analysis.

Main Results:

  • TrkB.T1 was identified as a truncated splice variant in human glioma.
  • TrkB.T1 enhances platelet-derived growth factor (PDGF)-driven gliomas in vivo.
  • TrkB.T1 augments PDGF-induced Akt and STAT3 signaling in vitro.
  • NGS implicated TrkB.T1 in PI3K signaling cascades independently of ligand binding.

Conclusions:

  • TrkB.T1 is a functional splice variant that promotes glioma progression.
  • The findings highlight the significance of including splice variant analysis in neuro-oncology research.
  • Expanding analyses beyond whole genes and gene fusions to include splice variants is crucial for basic and translational research.

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