Converging data from our individual laboratories support the notion that brain cancers (gliomas) are complex and dynamic ecosystems composed of several non-neoplastic cell types critical for glioma formation and maintenance. Specifically, we have shown that one of these non-neoplastic cell types (microglia) in the tumor microenvironment is a critical determinant of glioma cell growth and invasion. To more completely define the molecular mechanisms underlying tumor microenvironment regulation of glioma behavior, we have assembled a highly interactive team of researchers, including one early stage investigator focused on the tumor microenvironment (Dolores Hambardzumyan), one senior scientist expert in microglia-glioma interactions (Helmut Kettenmann), and two established physician-scientists (Eric Holland and David Gutmann) whose laboratories employ genetically engineered mouse models (GEMMs) to evaluate the dynamic interactions between non-neoplastic and neoplastic cells in glioma. Based on experimental findings from each of our individual laboratories, we hypothesize neoplastic glia (glioma cells) recruit and alter the function of resident brain microglia to create specialized tumor-associated microglia, that elaborate molecules that both create a permissive stroma (""""""""stromagenesis"""""""") (Aim 1) and activate astrocytes (Aim 2). These """"""""reactive"""""""" astrocytes support the creation and maintenance of the perivascular niche (gliomagens) (Aim 3), which provides the proper microenvironment for cancer stem cells - the treatment-resistant population of glioma cells (Aim 4). Collectively, this cross-disciplinary initiative capitalizes on converging lines of evidence that conceptualize gliomas as dynamic ecosystems composed of neoplastic and non-neoplastic cells and leverages expertise in mouse modeling, glioma biology, tumor microenvironment, microglia function, and translational medicine to identify new therapeutic targets for treating these deadly brain cancers.

Public Health Relevance

The grim prognosis and lack of therapeutic options for GBM highlights the urgency of developing new treatment modalities. GEM model of glioma will provide a unique opportunity to define the cells and molecular signals from the tumor microenvironment that contribute to gliomagenesis and continued growth relevant to the design of therapies aimed at eliminating the supportive niche provided by the tumor microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA160882-03
Application #
8730564
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mohla, Suresh
Project Start
2012-09-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja et al. (2016) Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling. J Neuropathol Exp Neurol 75:429-40
Hambardzumyan, Dolores; Gutmann, David H; Kettenmann, Helmut (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20-7
Hu, Feng; a Dzaye, Omar Dildar; Hahn, Alexander et al. (2015) Glioma-derived versican promotes tumor expansion via glioma-associated microglial/macrophages Toll-like receptor 2 signaling. Neuro Oncol 17:200-10
Feng, Xi; Szulzewsky, Frank; Yerevanian, Alexan et al. (2015) Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis. Oncotarget 6:15077-94
Gutmann, David H (2015) Microglia in the tumor microenvironment: taking their TOLL on glioma biology. Neuro Oncol 17:171-3
Szulzewsky, Frank; Pelz, Andreas; Feng, Xi et al. (2015) Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1. PLoS One 10:e0116644

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