DESCRIPTION (provided by applicant): Tumors of the brain are highly resistant to therapy. Primary glioblastomas are one of the most deadly tumors with a median survival of just over a year. When systemic cancer spreads to the brain the survival is particularly bleak because even though the systemic metastases can respond to therapy, the ones in the brain rarely do. One of the mechanisms for resistance of these tumors appears to be related to their vasculature and perivascular stromal cells since the cells that survive therapy are often perivascular and the perivascular niche is a location for stem-like resistant cells of the tumor. In this application we will investigate the role of vasculature and the stromal cells of the perivascular niche in primary and metastatic brain tumors. We will use a combination of engineered mouse models, human surgical samples, and human cell line to investigate the contribution of these cells to tumorigenesis and resistance to therapy. In project 1 we will investigate the expression patterns of these cell types in vivo in response to therapy and identify genes that predict response and survival in glioblastoma patients. In project 2 we will investigate the role of the vasculature on the ability for metastatic tumors to form in the brain and for these tumors to respond to therapy. In project 3 we will use genetic tools to modify the genetics of endothelial cells in a way to determine the contributions of angiocrine signaling in both primary and metastatic tumors to the brain.

RELEVANCE (See instructions): Glioblastoma is one of the most deadly cancers, and metastatic tumors to the brain are equally devastating and much more common. Both tumor types are highly resistant to therapy. Evidence suggests that one of the reasons for resistance of tumors in the brain resides in the blood vessels and cells surrounding them. We hope to understand the role of perivascular cells in therapeutic resistance to reverse this effect.