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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Fountain, Jane W
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Johns Hopkins University
Schools of Medicine
United States
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Kim, Jayoung; Shamul, James G; Shah, Sagar R et al. (2018) Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene glycol) Triblock Micelles for Cancer Therapy. Biomacromolecules 19:3361-3370
Jiang, Shanshan; Eberhart, Charles G; Lim, Michael et al. (2018) Identifying Recurrent Malignant Glioma after Treatment Using Amide Proton Transfer-Weighted MR Imaging: A Validation Study with Image-Guided Stereotactic Biopsy. Clin Cancer Res :
Shah, Sagar R; David, Justin M; Tippens, Nathaniel D et al. (2017) Brachyury-YAP Regulatory Axis Drives Stemness and Growth in Cancer. Cell Rep 21:495-507
Jiang, Shanshan; Eberhart, Charles G; Zhang, Yi et al. (2017) Amide proton transfer-weighted magnetic resonance image-guided stereotactic biopsy in patients with newly diagnosed gliomas. Eur J Cancer 83:9-18
Schiapparelli, Paula; Guerrero-Cazares, Hugo; MagaƱa-Maldonado, Roxana et al. (2017) NKCC1 Regulates Migration Ability of Glioblastoma Cells by Modulation of Actin Dynamics and Interacting with Cofilin. EBioMedicine 21:94-103
Guerrero-Cazares, Hugo; Lavell, Emily; Chen, Linda et al. (2017) Brief Report: Robo1 Regulates the Migration of Human Subventricular Zone Neural Progenitor Cells During Development. Stem Cells 35:1860-1865
Yang, Jr-M; Schiapparelli, P; Nguyen, H-N et al. (2017) Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization. Oncogene 36:3673-3685
Ravin, Rea; Blank, Paul S; Busse, Brad et al. (2016) Blast shockwaves propagate Ca(2+) activity via purinergic astrocyte networks in human central nervous system cells. Sci Rep 6:25713
Su, Hao; Zhang, Pengcheng; Cheetham, Andrew G et al. (2016) Supramolecular Crafting of Self-Assembling Camptothecin Prodrugs with Enhanced Efficacy against Primary Cancer Cells. Theranostics 6:1065-74
Capilla-Gonzalez, Vivian; Bonsu, Janice M; Redmond, Kristin J et al. (2016) Implications of irradiating the subventricular zone stem cell niche. Stem Cell Res 16:387-96

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