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

Siobhan S. Pattwell, Sonali Arora, Patrick J. Cimino, Tatsuya Ozawa, Frank Szulzewsky, Pia Hoellerbauer, Tobias Bonifert, Benjamin G. Hoffstrom, Norman E. Boiani, Hamid Bolouri, Colin E. Correnti, Barbara Oldrini, John R. Silber, Massimo Squatrito, Patrick J. Paddison and Eric C. Holland ()
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Siobhan S. Pattwell: Fred Hutchinson Cancer Research Center
Sonali Arora: Fred Hutchinson Cancer Research Center
Patrick J. Cimino: Fred Hutchinson Cancer Research Center
Tatsuya Ozawa: National Cancer Center Research Institute
Frank Szulzewsky: Fred Hutchinson Cancer Research Center
Pia Hoellerbauer: Fred Hutchinson Cancer Research Center
Tobias Bonifert: Fred Hutchinson Cancer Research Center
Benjamin G. Hoffstrom: Fred Hutchinson Cancer Research Center
Norman E. Boiani: Fred Hutchinson Cancer Research Center
Hamid Bolouri: Fred Hutchinson Cancer Research Center
Colin E. Correnti: Fred Hutchinson Cancer Research Center
Barbara Oldrini: Spanish National Cancer Research Centre
John R. Silber: University of Washington School of Medicine
Massimo Squatrito: Spanish National Cancer Research Centre
Patrick J. Paddison: Fred Hutchinson Cancer Research Center
Eric C. Holland: Fred Hutchinson Cancer Research Center

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Independent scientific achievements have led to the discovery of aberrant splicing patterns in oncogenesis, while more recent advances have uncovered novel gene fusions involving neurotrophic tyrosine receptor kinases (NTRKs) in gliomas. The exploration of NTRK splice variants in normal and neoplastic brain provides an intersection of these two rapidly evolving fields. Tropomyosin receptor kinase B (TrkB), encoded NTRK2, is known for critical roles in neuronal survival, differentiation, molecular properties associated with memory, and exhibits intricate splicing patterns and post-translational modifications. Here, we show a role for a truncated NTRK2 splice variant, TrkB.T1, in human glioma. TrkB.T1 enhances PDGF-driven gliomas in vivo, augments PDGF-induced Akt and STAT3 signaling in vitro, while next generation sequencing broadly implicates TrkB.T1 in the PI3K signaling cascades in a ligand-independent fashion. These TrkB.T1 findings highlight the importance of expanding upon whole gene and gene fusion analyses to include splice variants in basic and translational neuro-oncology research.

Date: 2020
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DOI: 10.1038/s41467-020-16786-5

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