Project 1 will follow up on initial observations that the diffuse character of these tumors is not simply due to the tumor cells migrating into the normal brain structures as had been previously thought but that the tumor actively recruits surrounding cells from the brain (brain stroma) and other sources into the tumor mass and induces their aberrant proliferation. These recruited stem/progenitor cells may function normally in the response to injury in a self-limiting manner. We will use lineage tracing combined with oncogenesis to genetically distinguish the progeny of the original tumor cells (marked by GFP expression) from the recruited cells. We will additionally use bioluminescence imaging to monitor the signaling activity of pathways known to drive stem/progenitor character in these recruited cells in slice preparations of tumors in situ. We have created reporter mice that express luciferase proportional to SHH, Wnt, and Notch signaling activity.
In Aim 1 we will determine the location from which the recruited cells arise, specifically the bone marrow and brain contribution. Our preliminary data indicates that a high percent of cells within gliomas are not derived from the original cell of origin and are recruited from other locations.
In Aim 2 we will determine whether loss of the known glioma tumor suppressors (INK4a, Arf, PTEN) will promote the incorporation and contribution of recruited cells to the tumor proper. In theory the recruited cells could acquire mutations independent from those found in the progeny of the cell of origin, and the cells making up the most malignant tumors could be derived from recruited cells.
In Aim 3 we will determine if the Gli-luc mouse line can be used for bioluminescence imaging to visualize recruitment and SHH signaling in gliomas overtime. The signaling pathways that attract recruited progenitor cells to the tumor and maintain them in proliferative and undifferentiated state are unknown.
Aim 4 we will determine if the SHH signaling and cell recruitment is a response to injury. Our preliminary data indicates that SHH signaling in gliomas is an in vivo phenomenon and that it may be a dysregulated response to injury that normally is tightly controlled temporally. We will systematically determine if SHH activation is part of a normal response to injury and if the alterations found in human gliomas that are known to induce gliomas in mice alter this effect.
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