Abstract A059: Integrative MR elastography and multi-omics identify conserved biomechanical states in adult diffuse gliomas

Abstract Molecular intratumoral heterogeneity is a defining feature of adult diffuse gliomas, yet how it relates to tissue biomechanics remains incompletely understood. Our prior magnetic resonance elastography (MRE) studies showed that regions of increased stiffness in glioblastoma are linked to extracellular matrix (ECM) remodeling and adverse prognosis, indicating that MRE captures key aspects of tumor physiology with prognostic value. Here, we extend this framework by integrating MRE with multi-omic profiling of multiregional tumor biopsies from adult diffuse gliomas to further characterize tissue mechanics and their relation to glioma biology. Using MRE, we show that local glioma mechanics can be summarized into three states—Soft-Fluidic, Soft-Elastic, and Stiff-Elastic—reflecting distinct combinations of stiffness and viscosity. Multiparametric MRI analyses demonstrate that these states map to discrete diffusion- and perfusion-defined microenvironments and localize to specific anatomical tumor compartments, indicating that they capture spatially organized intratumoral variation. Multi-omic analyses using mixed-effects linear models reveal molecular programs specific to each state. In IDH-wildtype glioblastomas, Stiff-Elastic regions correspond to active angiogenic sites with ECM synthesis and remodeling, including vascular collagens, and are enriched for proteins involved in cell contractility and adhesion as well as membrane-stabilizing lipid species, consistent with a mechanically reinforced microenvironment. In contrast, Soft-Elastic regions exhibit loss of fractional anisotropy, reduced vascular permeability, and depletion of both ECM components and membrane-stabilizing lipids. These regions harbor stress-responsive and hypoxia-associated malignant gene expression programs, potentially describing a hypoxic, metabolically constrained niche. Soft-Fluidic regions preferentially engage progenitor-like malignant states, including neuronal lineage programs, and display a glycolytic metabolic profile, consistent with a metabolically active compartment that supports cellular plasticity and turnover. In IDH-mutant gliomas, Stiff-Elastic regions showed transcriptional enrichment for ECM organization without the strong angiogenic or hypoxic signatures, and proteomic changes consistent with altered immune visibility and reduced membrane plasticity. In contrast, Soft-Fluidic and Soft-Elastic regions were enriched for triglycerides and proteins involved in cytoskeleton–membrane coupling. These findings indicate that while intratumoral mechanical states are conserved across glioma subtypes, their molecular composition differs with IDH status. Together, these results establish intratumoral tissue mechanics as a conserved axis of glioma heterogeneity that links noninvasive imaging to specific biophysical microenvironment states. More broadly, this work highlights MRE as a promising tool for probing glioma pathophysiology and provides a framework for incorporating tissue biomechanics into studies of tumor evolution, plasticity, and therapeutic vulnerability. Citation Format: Maksym Zarodniuk, Siri Fløgstad. Svensson, Skarphéðinn Halldórsson, Maria Gomez. Mahiques, Elies Fuster-García, Einar Osland. Vik-Mo, Kyrre Eeg. Emblem, Meenal Datta. Integrative MR elastography and multi-omics identify conserved biomechanical states in adult diffuse gliomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A059.