Diverse roles of Notch signaling in glioblastoma

New York University School Of Medicine, New York NY

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Abstract

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is an incurable brain malignancy with limited treatment options. Within GBM, cells with stem-like properties (GBM stem cells or GSCs) initiate and propagate tumors, and are highly resistant to conventional chemoradiotherapy. A major obstacle in understanding the biology of GSCs and developing therapies that directly target them has been the lack of molecular markers that universally identify them. Previous observations indicated that inhibition of Notch signaling, a pathway that regulates fate decisions in neuroglial development, attenuates but does not completely block the self-renewal of GSCs. These findings raise the possibility that Notch activation may be critical to some but not all GSCs, suggesting functional and molecular heterogeneity within the GSC compartment. Prior to Hurricane Sandy, we initiated a set of experiments aiming to clarify the identity of GBM cells in which Notch signaling is activated and understand their contribution to tumor heterogeneity during tumor growth and in response to chemotherapy. Using primary human GBM cultures genetically engineered to express fluorescent reporters in response to activation of Notch signaling, we discovered that, under in vitro conditions that favor GSC self-renewal, Notch is activated in cells that do not express CD133, a well-established cell surface marker of GSCs. Furthermore, we found that in vitro induction of differentiation increases the fraction of cells with activated Notch signaling. These findings raise important questions about the role of the Notch pathway in the cellular hierarchy of GBM: Does Notch signaling identify stem cells with tumor initiating properties or a different type of progenitor cells within GBM? What are the lineages that descend from cells in which Notch signaling is active in vivo? And how do these cells respond to chemotherapy treatment? Unfortunately, the storm inflicted substantial damage to our laboratory, including loss of our primary human GBM cultures. In addition, we had to re-establish our mouse colony in a new animal facility within NYU. Through this funding opportunity, we are requesting funds to extend our preliminary work to further understand the function on the Notch pathway in GBM. Our experiments will assess whether cells with active Notch signaling have tumor- initiating properties and what cell lineages they generate in vivo, including after treatment with the chemotherapeutic agent temozolamide, a mainstay in clinical management of GBM. We anticipate that our findings will generate a critical mass of data that will lead to a publication and a successful submission of an R01 proposal. Importantly, our findings will shed light on an important area of research within neuro-oncology and will facilitate the design of novel and informed therapeutic strategies.