TMIC-52. Clinical correlates of the diffuse glioma mechanical microenvironment - a systematic review

BACKGROUND Glioma progression and invasion is characterized by intricate tumor-microenvironment crosstalk. Numerous studies have shown influence of the mechanical properties of the tumor microenvironment, i.e. the mechanical microenvironment (MME), on glioma pathogenic features in vitro, such as cell migration, proliferation, and metabolism. The translational significance of these mechanistical insights remain poorly defined. We aim to assemble the existing evidence on the clinical relevance of the glioma MME. METHODS systematic review of the literature, in accordance with PRISMA-guidelines. Preclinical and clinical studies that reported clinically relevant correlates of the glioma MME were included. RESULTS We included 33 studies, comprising 19 clinical and 14 preclinical investigations. Tissue stiffness differed between healthy and tumor tissue, and across central nervous system tumors, glioma grades and molecular subtypes. Gliomas displayed marked heterogeneity in tissue stiffness, with some spatial concordance with histopathological hallmarks. Recurrent gliomas were stiffer than primary tumors. Recurrent glioblastomas interact with the MME, to sustain extracellular matrix (ECM) stiffening and tumor progression through PIEZO-1 and integrin feedback loops. Higher microenvironmental stiffness induced temozolomide resistance of glioma cells in 3D scaffolds in vitro. Tissue stiffness had a sensitizing effect for erlotinib, but not for doxorubicin. Multiple MME-properties correlated inversely to overall survival, including ECM-stiffness, associated tumoral mechanosignalling and gene expression, hyaluronic acid and tenascin C expression, a bulky glycocalyx, peritumoral tissue compression and an atypical collagen architecture. CONCLUSION MME properties and downstream mechanosignalling correlate to diagnostic classification of brain tumors, and clinical outcome in glioma patients. MME characteristics based on neuroimaging and molecular mechanoprofiling may predict treatment response. Manipulation of the MME may add to drug repurposing in glioma, by improving efficacy of existing drugs that have been ineffective to date. However, due to study heterogeneity, effective clinical translation demands robust validation, harmonized protocols, and thoughtful positioning of new strategies alongside established clinical practice.