Instructive Cues in Glioblastoma Hierarchies

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DESCRIPTION (provided by applicant): Glioblastomas are the most common primary brain tumor and the most lethal. Current glioblastoma therapy provides only palliation and these cancers are universally fatal. Although the concept of a tumor cell hierarchy remains controversial, increasing evidence supports the notion that subgroups of stem-like cancer cells contribute to tumor growth. These cancer stem cells stimulate the malignancy of tumor growth through preferential resistance to conventional therapies, stimulation of angiogenesis, and invasion into normal tissues. A central unexplained observation in the cancer stem cell hypothesis is the reestablishment of a cellular hierarchy despite growth advantages of the stem-like cells. Cancer stem cells express pro-differentiation factors, including bone morphogenetic proteins, which may promote the maintenance of differentiated tumor cells that provide signals in support of the cancer stem cells (e.g. Notch ligands, interleukin-6, and laminins). To determine potential microenvironmental interactions that maintain the cellular hierarchy, we interrogated secreted regulators of cellular differentiation that are associated with the cellular hierarchy. We find that glioblastoma stem cells express secreted antagonists of differentiation signals to maintain their growth. Further, forced expression of these molecules in non-stem tumor cells promotes stem-like features. The simultaneous expression of differentiating signals and their inhibitors may create tissue patterning with stem-like and differentiated populations, phenocopying development. As there is an association between expression of anti-differentiation signals and poor glioblastoma patient outcome, we hypothesize that targeting secreted inhibitors of microenvironmental differentiation cues may offer potential therapeutic benefit. The tumor microenvironment provides instructive cues to maintain the cellular hierarchy in both normal and neoplastic tissues; we are therefore developing a set of techniques to interrogate the cellular hierarchy in relevant microenvironments while representing appropriate molecular tumor phenotypes. Overall, this study will examine in vivo response of tumor cells to environmental influences such as bone morphogenic protein antagonists on the self-renewal and maintenance of stem cell-like tumor cells within their niche. Successful execution of this collaborative scientific endeavor promises to bring important new scientific insights into cancer biology, and may have profound implications for glioblastoma treatment paradigms.