PTPS-23: A NOVEL ROLE FOR NEUROTROPHIN SIGNALING IN PEDIATRIC ATYPICAL TERATOID RHABDOID TUMORS

Malignant rhabdoid tumors (MRTs) are among the most aggressive and lethal tumors in pediatric oncology, yet little is known about their underlying biology, prohibiting successful treatment outcomes. Aside from a commonly observed alteration in the SMARC1B tumor suppressor, these tumors are characterized by a remarkably high degree of genomic stability, suggesting that posttranslational modification, alternative splicing, or interactions with other tumor suppressors and growth factors may be involved. Attempts at modeling MRTs have proven difficult due to embryonic lethality of SMARC1B loss. One novel candidate for exploring MRT biology may lie within the neurotrophin family. Utilizing a unique approach employing the RCAS/TVA system - which allows for somatic transfer of genes into specific cell types - we have found that neurotrophin signaling influences the normative neurodevelopmental trajectory in wild-type mice when altered in nestin-positive cells. In the context of tumor suppressor loss (Ink4a/ARF deletion, PTEN loss), perturbations in neurotrophin signaling generate tumors that recapitulate the rhabdoid phenotype of a specific type of MRT found in the central nervous system, known as atypical teratoid rhabdoid tumor (AT/RT). In vivo analysis of downstream effectors such PI3K/Akt pathway targets, RhoA signaling, and transcription factors, further elucidate mechanistic links between neurotrophin signaling and AT/RT biology, while in vitro experiments quantify basic cellular functions implicated in tumorigenesis such as migration, proliferation, and apoptosis. Together these data uncover a novel role for neurotrophin signaling in AT/RT biology and may offer insight into therapeutic responses for treatments such as radiation and chemotherapy.