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Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells
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Oncogenic role of a developmentally regulated NTRK2 splice variant

Siobhan S Pattwell1,2,3, Sonali Arora1, Nicholas Nuechterlein4

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

Science Advances
|October 7, 2022
PubMed

Insights

The neurotrophin receptor splice variant TrkB.T1 plays a critical role in embryonic development and is implicated in various cancers. Its overexpression can drive tumor formation, highlighting its potential as an oncogene.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Oncology

Background:

  • Alternative splicing is crucial for development, but aberrant splicing can lead to disease.
  • The neurotrophin receptor TrkB has known roles in neuronal function.
  • Specific splice variants of TrkB may have distinct functions.

Purpose of the Study:

  • To investigate the role of the TrkB.T1 splice variant in neurodevelopment and cancer.
  • To identify the oncogenic potential of TrkB.T1.
  • To explore the signaling pathways associated with TrkB.T1.

Main Methods:

  • Analysis of NTRK2 isoform expression during embryonic development and in tumors.
  • Generation of mouse models with TrkB.T1 overexpression.
  • Affinity purification-mass spectrometry to identify TrkB.T1 interactors.
  • Analysis of signaling pathways including Wnt, TGF-β, Shh, and Ras.

Main Results:

  • TrkB.T1 is the predominant NTRK2 isoform during embryonic organogenesis.
  • Overexpression of TrkB.T1 in mice, under conditions of tumor suppressor loss, induced multiple solid and nonsolid tumors.
  • TrkB.T1 is highly expressed in various adult and pediatric tumors, including those with tropomyosin receptor kinase fusions.
  • TrkB.T1 interacts with key developmental and oncogenic signaling pathways.

Conclusions:

  • TrkB.T1 has a previously unrecognized role in neurodevelopment, embryogenesis, and oncogenesis.
  • TrkB.T1 functions as an oncogene with embryonic origins.
  • Understanding TrkB.T1's function offers new perspectives on developmental biology and cancer treatment.

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