Oncogenic role of a developmentally regulated NTRK2 splice variant

Menée in vitro et à l'aide de données des projets "The Cancer Genome Atlas" et "Therapeutically Applicable Research to Generate Effective Treatments", cette étude met en évidence le rôle oncogène du variant TrKB.T1 issu de l'épissage de l'ARN du récepteur NTRK2

Résumé en anglais

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. TrkB.T1 is oncogenic when overexpressed postnatally in many cell types that once expressed it during normal embryonic development.