The role of ECM-mediated mechanosignaling on regional immunosuppression in GBM

PROJECT SUMMARY (PROJECT 3 – CHEN) “The role of ECM-mediated mechanosignaling on regional immunosuppression in GBM” Recent studies reveal that immunosuppressive regions vary substantially throughout the heterogeneous glioblastoma (GBM) tumor microenvironment. These immune-restricted niches appear to correspond to specific extracellular matrix (ECM) components that are thought to drive regional mesenchymal transition. We hypothesize that these spatially distinct GBM mesenchymal regions both coincide with and are responsible for, monocytic myeloid-derived suppressor cell (M-MDSC) infiltration. Our COBRE project hypothesis predicts that changes in regional hyaluronic acid (HA) ECM stiffness induce the activation of proneural GBM cell surface CD44 that, in turn, drives mesenchymal transition and increases an M-MDSC recruiting/differentiation transcriptional program associated with cytokine secretion. Studies proposed in this phase 2 CCII COBRE application will (1) rigorously delineate the mechanistic pathway and effectors involved by focusing on a hypothesized HA→CD44→STAT3/ZEB1-dependent pathway and (2) delineate whether/how regional activation of this pathway results in a STAT3/ZEB1-dependent induction of IL-6/IL-17-mediated regional accumulation of M-MDSC-dependent immune suppression in GBM. We anticipate that results from this phase 2 COBRE project proposal will identify a new targetable axis and address a critical gap in our understanding of the impact of biophysical changes in GBM TME.