2. Academic Validation
  3. Oncogenic role of a developmentally regulated NTRK2 splice variant

Oncogenic role of a developmentally regulated NTRK2 splice variant

  • Sci Adv. 2022 Oct 7;8(40):eabo6789. doi: 10.1126/sciadv.abo6789.
Siobhan S Pattwell 1 2 3,  Sonali Arora 1,  Nicholas Nuechterlein 4,  Michael Zager 5 6,  Keith R Loeb 7 8,  Patrick J Cimino 1 8,  Nikolas C Holland 9 10,  Noemi Reche-Ley 11,  Hamid Bolouri 1 12,  Damian A Almiron Bonnin 1,  Frank Szulzewsky 1,  Vaishnavi V Phadnis 13,  Tatsuya Ozawa 14,  Michael J Wagner 7 15,  Michael C Haffner 1 7 8,  Junyue Cao 16,  Jay Shendure 5 17 18 19,  Eric C Holland 1 20
Affiliations

Affiliations

  • 1 Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop C3-168, Seattle, WA 98109, USA.
  • 2 Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA 98101, USA.
  • 3 Division of Pediatrics, Department Hematology/Oncology, University of Washington School of Medicine, Seattle, WA 98105, USA.
  • 4 Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA 98195, USA.
  • 5 Brotman Baty Institute for Precision Medicine, Seattle, WA 98195, USA.
  • 6 Center for Data Visualization, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • 7 Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
  • 8 Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, 325 9th Avenue, Box 359791, Seattle, WA 98104, USA.
  • 9 Center for Neural Science, New York University, 4 Washington Place, #809, New York, NY 10003, USA.
  • 10 Department of Psychiatry, Weill Cornell Medical College, 1300 York Ave, New York, NY 10065, USA.
  • 11 The Bush School, 3400 E Harrison St, Seattle, WA 98112, USA.
  • 12 Benaroya Research Institute, 1201 Ninth Avenue, Seattle, WA 98101, USA.
  • 13 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 14 Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 15 Division of Medical Oncology, University of Washington, 825 Eastlake Ave E., Seattle, WA 98109, USA.
  • 16 Rockefeller University, 1230 York Ave, New York, NY 10065, USA.
  • 17 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • 18 Allen Discovery Center for Cell Lineage Tracing, Seattle, WA 98195, USA.
  • 19 Howard Hughes Medical Institute, Seattle, WA 98195, USA.
  • 20 Seattle Tumor Translational Research Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
PMID: 36206341 DOI: 10.1126/sciadv.abo6789
Abstract

Temporally regulated alternative splicing choices are vital for proper development, yet the wrong splice choice may be detrimental. Here, we highlight a previously unidentified role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis, and forced overexpression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges as the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring tropomyosin receptor kinase fusions. Affinity purification-mass spectrometry proteomic analysis reveals distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, transforming growth factor-β, Sonic Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

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