Current glioma therapies only modestly prolong survival and therefore there is great interest in identifying new targets for glioma treatment. It s hypothesized that targeting cells in the tumor microenvironment such as microglia and macrophages may have therapeutic benefit. We are using genetic approaches to elucidate the actions of Macrophage Colony Stimulating Factor 1 (CSF1) in gliomagenesis. CSF1 is often expressed at high levels in high-grade human gliomas. The CSF1 receptor, CSF1R, is expressed on macrophages including brain resident macrophages that are called microglia. Microglia and/or peripherally derived macrophages are a major component of the microenvironment in high-grade gliomas. In some human gliomas, CSF1R is also expressed on tumor cells, suggesting a possible additional autocrine role for CSF1 signaling in gliomagenesis. One small molecule inhibitor of CSF1R is in clinical trials for glioma. However, the actions of CSF1 signaling on glioma initiation and progression in vivo have not previously been studied in a genetically tractable system. CSF1 signaling through CSF1R can promote multiple cellular responses including proliferation, migration, survival or differentiation. Therefore, in order to understand the therapeutic implications of CSF1R blockade, it is important to elucidate the impacts of both autocrine and paracrine CSF1 signaling during gliomagenesis in vivo. Specifically, the proposed research will determine the roles of CSF1 and CSF1R in glioma initiation and progression in a transgenic mouse glioma model. The impact of CSF1 on phenotypes of glioma-associated macrophages/microglia will be determined. Genetic gain- and loss-of-function experiments in mice will be used to dissect autocrine and paracrine CSF1 actions during gliomagenesis. The contribution of CSF1 autocrine signaling to human glioma cancer stem cell proliferation and survival will also be investigated. The ability of CSF1R blockade to impact the numbers and phenotypes of glioma-associated macrophages/microglia will be determined and the ability of CSF1 or CSF1R levels to influence response to CSF1R-directed therapy tested. The impacts of CSF1R specific and non-specific inhibitors on other tumor-associated immune cells will be determined, as will the ability of CSF1R inhibition to cooperate with a standard chemotherapeutic. In summary, the work proposed here includes detailed in vivo studies to elucidate the biological effects of CSF1 autocrine and paracrine signaling in gliomagenesis; and to determine how to best exploit CSF1 signaling as a target for glioma therapy. As high levels of CSF1 are found in multiple CNS diseases, the results of this study may have therapeutic implications in many CNS pathologies.
Gliomas are devastating tumors that desperately need better therapies. We are studying a signaling molecule that is over-expressed in gliomas and has important actions on both glioma cells and glioma-infiltrating immune cells. This study will further explore how this signaling molecule influences glioma development and how drugs that block its actions may be best exploited for glioma therapy.
|De, Ishani; Steffen, Megan D; Clark, Paul A et al. (2016) CSF1 Overexpression Promotes High-Grade Glioma Formation without Impacting the Polarization Status of Glioma-Associated Microglia and Macrophages. Cancer Res 76:2552-60|
|Vyazunova, Irina; Maklakova, Vilena I; Berman, Samuel et al. (2014) Sleeping Beauty mouse models identify candidate genes involved in gliomagenesis. PLoS One 9:e113489|