Abstract PR06: CSF1 signaling is a potential therapeutic target for glioma
Authors: De Ishani , Steffen Megan D. , Sokn Emily , Patros Clayton , Litscher Suzanne , Clark Paul A. , Kuo John S. , Rodriguez Fausto J. , Collier Lara S. 
Published: May 2016

Current therapies for high-grade gliomas only modestly extend survival. Given that intrinsic characteristics of glioma cancer stem cells (gCSCs) make them hard to effectively target with current therapies, cells in the tumor microenvironment such as microglia/macrophages are being investigated as therapy targets. We previously identified a microglial/macrophage growth factor, Macrophage colony stimulating factor (Csf1), as a candidate glioma oncogene in a mouse somatic mutagenesis screen. CSF1 overexpression, CSF1 receptor (CSF1R) overexpression, and phosphorylated CSF1R have also been detected in human gliomas. We are using genetic and pharmacological strategies to investigate the role of CSF1 signaling in gliomagenesis in immunocompetent autochthonous mouse models to examine the therapeutic utility of targeting the CSF1R signaling axis. To determine the relevant CSF1R ligand(s) in human gliomas, we performed semi-quantitative RT-PCR on patient-derived gCSCs to examine expression of splice variants encoding membrane bound or secreted CSF1 as well as the additional CSF1R ligand IL34. We found that gCSCs primarily express the mRNA splice variant encoding secreted CSF1, but a splice variant encoding a membrane bound form was also detected. Most gCSCs lines did not express detectable levels of IL34 mRNA. We therefore developed a tissue-specific secreted CSF1 overexpressing transgenic model to study the effect of modulating CSF1 levels in the central nervous system. Since CSF1 is a growth factor for microglia, we previously studied the effects of increased CSF1 levels on microglial phenotypes and found that CSF1 overexpression increased microglial numbers and promoted microglial proliferation in vivo, but did not inherently polarize microglia toward a M2-like phenotype. Moreover, CSF1 signaling is required for survival of adult microglia in vivo, since inhibition of CSF1 signaling by the small molecule inhibitor PLX3397 induced microglial apoptosis. We now show that CSF1 overexpression accelerates gliomagenesis in a genetic model of spontaneous gliomagenesis driven by activated Ras. Both high- and low-grade gliomas form in mice with activated Ras, but CSF1 overexpression causes a dramatic increase in the percentage of tumors that are high-grade. Additionally, gliomas do not form in mice expressing activated Ras that are also CSF1-deficient. Therefore our data in this in vivo model indicate that CSF1 signaling plays a fundamental role in glioma development. Additional studies are underway to determine the impact of CSF1 on microglial and glioma phenotypes, and to explore how to best target CSF1 signaling for glioma therapy.

Citation Format: Ishani De, Megan D. Steffen, Emily Sokn, Clayton Patros, Suzanne Litscher, Paul A. Clark, John S. Kuo, Fausto J. Rodriguez, Lara S. Collier. CSF1 signaling is a potential therapeutic target for glioma. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr PR06.