Glioblastoma (GBM) remains among the most formidable cancers to treat, and current therapies, including radiation and temozolomide chemotherapy, have only palliative effects. Tumor recurrence occurs in virtually all patients, and relapsed tumors are more resistant to current cytotoxic therapies. Recent robust transcriptional profiling has classified GBM into 4 subtypes with distinct clinical features. In particular, mesenchymal (MES) GBM appears to be the most common subtype with the poorest prognosis. Nonetheless, the mechanisms that regulate growth of MES GBM cells have not been clarified. Among the heterogeneous cells in tumors, glioma stem cells (GSCs) are one of the, if not the only, critical therapeutic targets;however, subtype-specific GSCs are poorly characterized. Our preliminary data suggest the following: a- mesenchymal, but not proneural, GSCs express CD44v6;b- siRNA for CD44v6 reduces in vitro growth of MES, but not PN GSCs;c- CD44v6(+) cells but not CD44v6 (-) cells in mesenchymal GSCs express the neural stem cell-associated gene MELK;d- siRNA for CD44v6 reduces MELK expression;e- CD44 locus exhibits multiple Musashi 1 (Msi1)-binding sequences;f- shRNA- mediated Msi1 depletion diminishes CD44 expression and negatively affects splicing of exon v6. To achieve the goals of this study, we established and characterized patient-derived GBM sphere cultures and created patient-derived mouse GBM tumor models that recapitulate the histopathology of the original tumors. With these pre-clinical models, we will test the hypothesis that the Msi1-CD44v6 signaling is required for the growth and survival of therapy-resistant mesenchymal glioblastoma. Specifically, in Aim 1, we will test the hypothesis that CD44v6 is functionally essential for the proliferation of MES GSCs through signal interaction with MELK.
In Aim 2, we will determine whether CD44 transcripts are a direct target of the RNA-binding protein Msi1 in GBM and if Msi1 via the axis CD44v6-MELK plays a role in radio-resistance.

Public Health Relevance

The most common type of adult primary brain tumors, GBM is a devastating disease, and recurrence occurs in almost all patients. Although some cancers may not conform to the cancer stem cell model, evidence suggests that in GBM, glioma stem cells (GSCs) are responsible for glioma propagation, maintenance, resistance to conventional therapy, and tumor recurrence. This proposal will molecularly define GSCs by characterization of the key mechanism underlying proliferation of GSCs. We will further determine whether elimination of GSCs attenuates growth of tumors with the pre-clinical patient-derived GBM models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA175875-01A1
Application #
8636104
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Watson, Joanna M
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$211,494
Indirect Cost
$50,848
Name
Ohio State University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A et al. (2017) MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer Cell 32:840-855.e8
Wang, Jia; Cheng, Peng; Pavlyukov, Marat S et al. (2017) Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. J Clin Invest 127:3075-3089
Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885
Kim, Sung-Hak; Ezhilarasan, Ravesanker; Phillips, Emma et al. (2016) Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-?B-dependent Manner. Cancer Cell 29:201-13
de Araujo, Patricia Rosa; Gorthi, Aparna; da Silva, Acarizia E et al. (2016) Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit. Am J Pathol 186:2271-8
Uren, Philip J; Vo, Dat T; de Araujo, Patricia Rosa et al. (2015) RNA-Binding Protein Musashi1 Is a Central Regulator of Adhesion Pathways in Glioblastoma. Mol Cell Biol 35:2965-78
Cheng, Peng; Phillips, Emma; Kim, Sung-Hak et al. (2015) Kinome-wide shRNA screen identifies the receptor tyrosine kinase AXL as a key regulator for mesenchymal glioblastoma stem-like cells. Stem Cell Reports 4:899-913
Nakano, Ichiro; Garnier, Delphine; Minata, Mutsuko et al. (2015) Extracellular vesicles in the biology of brain tumour stem cells--Implications for inter-cellular communication, therapy and biomarker development. Semin Cell Dev Biol 40:17-26
Nakano, Ichiro (2015) Stem cell signature in glioblastoma: therapeutic development for a moving target. J Neurosurg 122:324-30

Showing the most recent 10 out of 25 publications