TMIC-43. A TENSION-MEDIATED GLYCOCALYX FEEDBACK LOOP PROMOTES A MESENCHYMAL, STEM-LIKE PHENOTYPE IN GLIOBLASTOMA. (5th November 2018)

• Record Type: Journal Article
• Authors: Kaushik, Shelly; Barnes, James Matthew; Bainer, Russell O; Sa, Jason K; Woods, Elliot C; Kai, FuiBoon; Przybyla, Laralynne; Lakins, Jonathon N; Phillips, Joanna J; Nam, Do-Hyun; Bertozzi, Carolyn R; Weaver, Valerie M
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi265
• Page End: vi266
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1102
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma multiforme (GBM) is one of the deadliest central nervous system cancers, difficult to treat and largely impossible to cure. A considerable challenge in GBM therapy is treatment resistance and tumor recurrence, resulting in dismal patient prognosis. GBM aggression is often associated with a mesenchymal phenotype, increased expression of glycoproteins and the presence of tumor-initiating "stem-like" cells. Using patient-derived xenograft models, and immune competent syngeneic and transgenic glioma mouse models, we show that GBMs demonstrate increased contractility, and their tumors are surrounded by a stiffer ECM, that maintains and even further enhances integrin mechanosignaling. As a result of increased integrin signaling, these tumors also harbor a mesenchymal-like gene signature and phenotype, possess a bulky glycocalyx and demonstrate a stem-like phenotype. Bioinformatics analysis, expression profiling and limiting dilution studies reveal that these mechanically challenged tumors express more "bulky" glycoproteins such as mucins and CD44, as well as glycocalyx regulators, galectins. Considering that a large proportion of these bulky glycoproteins are also stem markers, we show that upregulation of the glycoproteins and their modulators leads to enhanced GBM stem-ness. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignaling and a bulky glycocalyx, which promotes a mesenchymal, stem-like phenotype in GBMs. Thus, therapeutic strategies to target GBM tissue tension could reduce mortality and improve patient outcome.