Role of NKCC1 on Brain Tumor Stem Cell Migration After EGF and Slit-2 Stimulation

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DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and devastating intracranial malignant tumor accounts for 20% of all primary brain tumors and has a median survival rate of only 14 months. Cancer cells often disseminate far from primary tumors and individual glioma cells migrate from the gross tumor into the surrounding parenchyma, making complete surgical resection nearly impossible. This migratory capacity of malignant gliomas represents the greatest challenge to any potential therapy in spite of advances in surgery, chemotherapy and radiotherapy and growth of the remaining invasive cells leads to a recurrence incidence of 99%. What exactly regulates the migratory capacity of brain tumor cells is not fully understood and need to be studied. The main goal of this proposal is to understand the link between known pro- migratory signals such as epidermal growth factor (EGF) and Slit proteins with cell volume regulation. EGF and Slit proteins may play an important role in the modulation of invasive and migratory ability of GBM derived stem cells through Akt pathway that in turn regulates the activation of ion cotransport NKCC1. We propose to study invasive patterns and cell volume changes resulting in the extension of a leading process of a migrating cell, using various cell migration assays and measuring intracellular anion concentration. The results obtained from this work will help us understand the downstream signaling pathways involved in the activation of cascade mechanism responsible for brain tumor cell migration. Further, such knowledge will undoubtedly result in better therapeutic alternatives to current sub-optimal treatments for this devastating disease. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM) is the most common and devastating primary malignant tumor. Our project aims to study the migration of GBM-derived Brain Tumor Stem Cells (BTSCs). BTSCs are thought to be responsible for maintaining the bulk of the tumor and to induce recurrence after surgical resection, nevertheless the molecular mechanisms that regulate their migration are not known. In this study, we propose to understand the role of pro-migratory signals in brain tumor invasion in order to increase the available targets to prevent brain tumor dispersal.