Patients with high grade glioblastoma multiforme (GBM) have a mean survival time of 6-12 months due to the relative ineffectiveness of radio and chemotherapy and diffuse invasion into healthy brain tissue. Although the exact """"""""apex cell"""""""" of origin for any GBM subtype remains uncertain, there is reasonable consensus that the most aggressive GBMs arise from stem cells, or at the very least from pluripotent cells. Overwhelming majority of GBM research to date has focused on GBM cell's unique genetic and biochemical signaling components with little or no focus on the biophysical features. Work proposed here aims to characterize the cell-intrinsic biophysical features of GBM cells that render them aggressive. Successful completion of this interdisciplinary work has the potential to offer a new paradigm with which to clarify the basis for enhanced survival, invasiveness, and treatment resistance of GBMs. Objectives: The long term goal of proposed work is to reveal more effective GBM treatment modalities, extend patient survival, and improve the quality of life for GBM patients by integrating physical scientist's concepts with the basic and clinical cancer biology research in order to explore the role of cell-intrinsic force in GBM aggression. Specifically, since aggressive nature of GBMs has been attributed to their stem-like properties, the proposal tests the idea that stemness and death-resistant behavior is mediated though a unique cell-intrinsic mechano-phenotype due to altered glycocalyx, the cell-associated carbohydrate layer, and interrogates the molecular mechanism responsible for its upregulation, which is hypothesized to act through NCoR2 and Notch. Overview of Approach: Proposed work tests a functional link between Notch and NCoR2 signaling and elucidates whether their combined action synergistically drives deposition of high levels glycoproteins at the cell surface which can in turn drive integrin and notch activation by biophysical means to modify survival, invasion, and treatment resistance. Techniques such as traction force, scanning angle interference, TIRF, second harmonic generation, spinning disc, and laser confocal microscopies will be used to characterize the biophysical properties of WT human GBM cells as well those with modified NCoR2 or Notch. To interrogate the mechanism sustaining these stem-like properties in vitro, genetic engineering of GBM cells and biomaterial engineering strategies will be used. Orthotopic xenograft mouse models of human GBMs will be employed to test the effectiveness of targeting NCoR2-Notch-glycocalyx circuitry in vivo.
Proposed research will contribute to the understanding and targeting of the critical pathways sustaining GBM aggressiveness. Ultimately, the aim of proposed studies is to elucidate the relative contribution of cellular biophysical properties to tumor cell aggressiveness and survival in order to reveal new and more effective avenues for GBM therapy and address the hugely unmet clinical need for GBM patients, thereby contributing to NIH's mission which seeks to improve human health. PROJECT NARRATIVE Glioblastoma multiforme (GBM) is the most common and deadly form of adult glioma that is associated with median survival rate of fifteen months due to the relative ineffectiveness of current standard-of-care treatment modalities. There remains a tremendous unmet clinical need for effective therapeutics for GBM patients and because the role of mechanical forces in GBM cell behavior has not been directly investigated, proposed studies are of great importance. Proposed work will equip researchers with a greater understanding of the biophysical mechanisms driving enhanced survival and treatment resistance of GBMs and identify novel, druggable, mechanically-sensitive signaling pathways which could be targeted in order to increase GBM patient survival and enhance their quality of life.
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