Glioblastoma (GBM) is an almost universally fatal brain tumor with an average median survival of only ~15 months. New effective therapies are desperately needed. Small subpopulations of malignant cells with stem cell-like properties exist in GBM. These neoplastic stem-like cells (GBM SCs) are distinguishable from the majority of tumor cells by their relative resistance to DNA damaging agents, and their ability to efficiently propagate tumor xenografts in experimental animals. GBM SCs are believed to be responsible for GBM resistance to current therapies. The long-term objectives of this proposal are to understand the mechanisms that support GBM SCs since advances in treating GBM will likely depend upon targeting these mechanisms. Specific transcription factors (TFs) such as Sox2, Oct4, and Nanog, have essential roles in maintaining the stemness and proliferation potential of normal neural stem cells. In addition, the forced expression of these and other TFs (e.g. c-Myc, KLF4) can induce or """"""""reprogram"""""""" somatic cells into pluripotent stem (iPS) cells. Similarities between iPS cells and GBM SCs suggest our hypothesis that stem cell reprogramming transcription factors and pathways that induce their expression/function play a major role in the formation and/or tumor propagating capacity of GBM SCs. This hypothesis is specifically supported by preliminary data linking oncogenic c-Met signaling to the GBM SC phenotype and the expression of stem cell reprogramming factors. The experiments outlined in this proposal will rigorously examine the c-Met signaling supports the pool of tumor-initiating GBM SCs via transcriptional reprogramming mechanisms.
Aim #1 will determine spatial/temporal relationships between the SC phenotype, reprogramming TF expression, and c-Met in newly diagnosed and recurrent GBM.
Aim #2 will determine the roles for Oct4 and Nanog in the induction of GBM cell stemness by c-Met.
Aim #3 will identify Nanog transcription targets in GBM-CSCs.
Aim #4 will determine the effects of in vivo c-Met inhibition on reprogramming mechanisms and GBM cell stemness. These experiments are timely, of high potential impact, and clinically relevant. Positive results will uncover a previously unknown link between stem cell reprogramming mechanisms induced by oncogenic c-Met signaling and the tumor-initiating stem-like phenotype. Results will alter current paradigms regarding neoplastic stem cell biology and provide valuable information for optimizing the clinical development of stem cell targeting brain cancer therapy, and pharmacologic inhibitors of c-Met and other oncogenic reprogramming pathways.

Public Health Relevance

Glioblastoma is a very aggressive and almost universally fatal brain tumor. Malignant stem-like cells are believed to be responsible for the resistance of glioblastoma to current therapies. This project will identify new therapeutic vulnerabilities of glioblastoma stem cells by determining how they are supported and regulated by the receptor tyrosine kinase c-Met and reprogramming transcription factors.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Fountain, Jane W
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Hugo W. Moser Research Institute Kennedy Krieger
United States
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Lopez-Bertoni, Hernando; Kozielski, Kristen L; Rui, Yuan et al. (2018) Bioreducible Polymeric Nanoparticles Containing Multiplexed Cancer Stem Cell Regulating miRNAs Inhibit Glioblastoma Growth and Prolong Survival. Nano Lett 18:4086-4094
Oyinlade, Olutobi; Wei, Shuang; Lal, Bachchu et al. (2018) Targeting UDP-?-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration. Oncogene 37:2615-2629
Coulter, Jonathan B; Lopez-Bertoni, Hernando; Kuhns, Katherine J et al. (2017) TET1 deficiency attenuates the DNA damage response and promotes resistance to DNA damaging agents. Epigenetics 12:854-864
Sun, Han; Luo, Liqun; Lal, Bachchu et al. (2016) A monoclonal antibody against KCNK9 K(+) channel extracellular domain inhibits tumour growth and metastasis. Nat Commun 7:10339
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Lopez-Bertoni, Hernando; Li, Yunqing; Laterra, John (2015) Cancer Stem Cells: Dynamic Entities in an Ever-Evolving Paradigm. Biol Med (Aligarh) 7:
Lee, Eun-Joon; Rath, Prakash; Liu, Jimei et al. (2015) Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells. J Genet Genomics 42:355-71
Lopez-Bertoni, H; Lal, B; Li, A et al. (2015) DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene 34:3994-4004
Sun, Peng; Xia, Shuli; Lal, Bachchu et al. (2014) Lipid metabolism enzyme ACSVL3 supports glioblastoma stem cell maintenance and tumorigenicity. BMC Cancer 14:401
Sagal, Jonathan; Zhan, Xiping; Xu, Jinchong et al. (2014) Proneural transcription factor Atoh1 drives highly efficient differentiation of human pluripotent stem cells into dopaminergic neurons. Stem Cells Transl Med 3:888-98

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