Neurosurgical Oncology Unit

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

INTRODUCTION: Glioblastoma is the most common primary malignant brain tumor. The disease is uniformly fatal with a median overall survival of only 15 months. The current standard of care for newly diagnosed glioblastoma is maximal safe resection, radiotherapy, and temozolomide. The primary cilium is a microtubule-based organelle present on the apical surface of nearly all mammalian cells critical to many canonical signaling pathways and closely related to the cell cycle. They are implicated in the formation and progression of many malignancies and associated with resistance to chemoradiotherapy. RESULTS: Patient-derived GBM cell lines were transduced with lentiviral particles to produce stable cell lines deficient in KIF3A, an important protein in ciliogenesis. Cell proliferation assays were used to assess sensitivity to radiotherapy and wound healing assays were used to assess cell migration. We confirmed that several characteristics of primary human glioblastoma proliferation of human glioblastoma cells are altered following KIF3A knockdown. A bioinformatics approach was also utilized to evaluate the impact of cilia-related gene expression on patient survival using two unrelated publicly available databases. 2023 Update: We have shown that blocking ciliogenesis via knockdown of different genes required for ciliogenesis, results in impaired ability of glioblastoma cells to induce myeloid-derived suppressor cells which are used for glioblastoma-mediated immunosuppression. This is a novel connection between primary cilia and cancer immunosuppression pathways. 2024 Update: We have shown that primary cilia are necessary for expression of IL-6 in glioblastoma. This expression in part orchestrates the tumor-mediated immunosuppression through release and differential packaging of tumor derived extracellular vesicles. Our work has also shown that low-grade gliomas differentially regulate primary cilia genes and that this differential regulation has utility for deepening our molecular understanding of pathogenesis. CONCLUSIONS: Collectively, our findings provide strong evidence that primary cilia play an important role in glioma pathogenesis. These findings will form the basis for continued development for novel prognostic markers and treatments for glioblastomas and gliomas. Furthermore, primary cilia signaling may be used to enhance response to immunotherapy in glioblastoma and potentially other tumor types. Please note the lab will be closing 9/30/2025.Primary research activity will cease on that date and efforts will then be turned to publishing all data