Research And Grants

Tumor Associated Microglia in Diffuse Intrinsic Pontine Glioma

Diffuse high-grade gliomas are a class of central nervous system tumors that carry a dismal prognosis across all ages. In children, about half of these tumors arise within the ventral pons as diffuse intrinsic pontine glioma (DIPG), which has a peak incidence from ages 6-8 and only a 9-12 month median survival. The consistent timing and location of this tumor suggests that specific developmental cues in the microenvironment of the mid-childhood ventral pons may be dysregulated. Microglia, the resident macrophages of the brain, represent both a component of the normal developmental microenvironment and also a potential contributor to pathologic microenvironments such as DIPG. Tissue macrophages are critical in the development of other organs (Pollard, 2009), and recent studies suggest that microglial trophic factors play a role in development and learning (Ueno et al., 2013; Parkhurst et al., 2013). In adult gliomas, macrophages can make up 30-50% of the tumor mass and are implicated as supporting angiogenesis and tumor cell invasion, proliferation, and survival (Glass & Synowitz, 2014). In contrast to adult gliomas, however, strikingly little is known about how microglia and macrophages contribute to the pediatric high-grade glioma microenvironment. Given the possible role of microglia in normal brain development, an intriguing hypothesis is that these pediatric gliomas hijack normal supportive roles of microglia to promote tumor growth and invasion. Understanding this interaction in molecular detail will provide insight not only into the pathophysiology of DIPG and possible adjuvant therapeutic targets, but also into the possible roles of microglia in normal brain development.
This research proposal seeks to elucidate the mechanisms through which microglia interact with DIPG. Previous work demonstrated that inhibition of colony stimulating factor-1 signaling in macrophages in a murine glioblastoma model can block glioma progression (Pyonteck et al., 2013). Moreover, recent evidence suggests that adult glioblastomas secrete the soluble factor periostin, which attracts macrophages and directs them to promote tumor growth (Zhou et al., 2015). In primary DIPG tissue samples, there is a high degree of microglial staining (Figure 1, Caretti et al., 2014), which suggests that these cells play an important role in shaping the DIPG microenvironment. Determining how this microglial role differs in DIPG compared to adult gliomas will provide a better understanding of the role of microglia in the unique midchildhood pontine microenvironment.
We hypothesize that pontine microglia promote DIPG growth through secreted growth factors, and we propose to test this hypothesis through the following aims:
1) Demonstrate how pontine microglia affect DIPG behavior at baseline and in various states of activation.
2) Identify the molecular signals that underlie microglial
effects on DIPG proliferation.
3) Determine what pathways are activated in DIPG by microglial-secreted factors.
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