Oncogenic role of a developmentally regulated NTRK2 splice variant

Abstract Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-ß, 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.摘要 受时间精确调控的可变剪接选择对于正常发育至关重要，而错误的剪接选择则可能带来有害后果。本研究揭示了神经营养因子受体剪接变体TrkB.T1在人类与小鼠的多种肿瘤类型中，于神经发育、胚胎发生、细胞转化及肿瘤发生过程中的全新功能。TrkB.T1是胚胎器官发生阶段占主导的神经营养性酪氨酸受体激酶2（NTRK2）同工型；在肿瘤抑制因子缺失的背景下，强制过表达该胚胎特异性剪接模式可在小鼠体内诱发多种实体瘤与非实体瘤。此外，TrkB.T1亦是成人及儿童多种肿瘤中主导表达的NTRK同工型，其中涵盖携带TRK融合突变的肿瘤。通过亲和纯化-质谱联用蛋白质组学（Affinity purification-mass spectrometry, AP-MS）分析，研究发现TrkB.T1拥有独特的互作蛋白组，可与Wnt、转化生长因子β（TGF-β）、刺猬信号通路（Hedgehog）及Ras等已知的发育与致癌信号通路产生相互作用。从剪接因子的改变到基因表达的变化，这类携带有胚胎起源的同工型特异性致癌基因的发现，有望重塑我们对于发育系统及肿瘤学的认知范式。