Tumor Microenvironment Interactions in Brain Tumors

Sloan-Kettering Inst Can Research, New York NY

Investigators

Linked publications & trials

Abstract

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