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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Müller-Greven, Gaëlle; Carlin, Cathleen R; Burgett, Monica E et al. (2017) Macropinocytosis of Bevacizumab by Glioblastoma Cells in the Perivascular Niche Affects their Survival. Clin Cancer Res 23:7059-7071
Chen, Zhihong; Feng, Xi; Herting, Cameron J et al. (2017) Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma. Cancer Res 77:2266-2278
Herting, C J; Chen, Z; Pitter, K L et al. (2017) Genetic driver mutations define the expression signature and microenvironmental composition of high-grade gliomas. Glia 65:1914-1926
Pan, Yuan; Smithson, Laura J; Ma, Yu et al. (2017) Ccl5 establishes an autocrine high-grade glioma growth regulatory circuit critical for mesenchymal glioblastoma survival. Oncotarget 8:32977-32989
Pitter, Kenneth L; Tamagno, Ilaria; Alikhanyan, Kristina et al. (2016) Corticosteroids compromise survival in glioblastoma. Brain 139:1458-71
Szulzewsky, Frank; Arora, Sonali; de Witte, Lot et al. (2016) Human glioblastoma-associated microglia/monocytes express a distinct RNA profile compared to human control and murine samples. Glia 64:1416-36
Hambardzumyan, Dolores; Gutmann, David H; Kettenmann, Helmut (2016) The role of microglia and macrophages in glioma maintenance and progression. Nat Neurosci 19:20-7
Dzaye, Omar; 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
Feng, Xi; Szulzewsky, Frank; Yerevanian, Alexan et al. (2015) Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis. Oncotarget 6:15077-94
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

Showing the most recent 10 out of 19 publications