Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

Abstract

Gliomas represent the most common malignant primary brain tumors, and a high-grade subset of these tumors including glioblastoma are particularly refractory to current standard-of-care therapies including maximal surgical resection and chemoradiation. The prognosis of patients with these tumors continues to be poor with existing treatments and understanding treatment failure is required. The dynamic interplay between the tumor and its microenvironment has been increasingly recognized as a key mechanism by which cellular adaptation, tumor heterogeneity, and treatment resistance develops. Beyond ongoing lines of investigation into the peritumoral cellular milieu and microenvironmental architecture, recent studies have identified the growing role of mechanical properties of the microenvironment. Elucidating the impact of these biophysical factors on disease heterogeneity is crucial for designing durable therapies and may offer novel approaches for intervention and disease monitoring. Specifically, pharmacologic targeting of mechanical signal transduction substrates such as specific ion channels that have been implicated in glioma progression or the development of agents that alter the mechanical properties of the microenvironment to halt disease progression have the potential to be promising treatment strategies based on early studies. Similarly, the development of technology to measure mechanical properties of the microenvironment in vitro and in vivo and simulate these properties in bioengineered models may facilitate the use of mechanical properties as diagnostic or prognostic biomarkers that can guide treatment. Here, we review current perspectives on the influence of mechanical properties in glioma with a focus on biophysical features of tumor-adjacent tissue, the role of fluid mechanics, and mechanisms of mechanical signal transduction. We highlight the implications of recent discoveries for novel diagnostics, therapeutic targets, and accurate preclinical modeling of glioma.

Cuproptosis key gene FDX1 is a prognostic biomarker and associated with immune infiltration in glioma

“…To further explore the correlation between FDX1 expression and clinical characteristics of glioma patients. Online tool GEPIA 9 was used to performed the survival analysis of LGG and GBM samples. The results showed that FDX1 expression was associated with overall survival (OS) and progression-free survival (PFS) in patients with low-grade glioma, but not with OS or PFS in GBM patients (Figure 4A).…”

“…Glioma is one of the most common central nervous system malignancies (1)(2)(3)(4)(5)(6). Evidence shows that high-grade glioma (HGG) has obvious aggressiveness and heterogeneity (7)(8)(9)(10)(11)(12)(13)(14). In 2022, the World Health Organization (WHO) updated the classification criteria of glioma according to the molecular characteristics of different gliomas, which will help patients obtain more accurate diagnoses and precise personalized treatment in clinical practice (1,2).…”

Characterization of aging cancer-associated fibroblasts draws implications in prognosis and immunotherapy response in low-grade gliomas

“…Differentially enriched functions between the two aging CAF score groups were analyzed to explore the underlying molecular mechanisms. We found that stroma-related functions were active in the high-aging CAF score group, including fibronectin binding, collagen binding, ECM receptor interaction, focal adhesion, and cell adhesion molecule (CAM)-related pathways, which may contribute to tumorigenesis and progression ( Walker et al, 2018 ; Winkler et al, 2020 ; Bhargav et al, 2022 ) ( Figures 4J,K ).…”

Substrate stiffness effect on molecular crosstalk of epithelial-mesenchymal transition mediators of human glioblastoma cells

“…For instance, reports using confined compression ( 45 ) or ultrasound-based shear wave elastography ( 46 ) showed that GBM tumor tissues were stiffer than normal brain, whereas a study using shear compression reported no differences ( 47 ). Moreover, most reports agree that stiffness in the GBM tissue increases, but whether if it is ascribed to changes within the ECM, to an increased interstitial pressure, to the cells, or their combination is still under study ( 48 ). Also, numerous studies have reported the ECM stiffness to influence GBM invasion and proliferation, and to regulate cell cycle progression and proliferation through EGFR-dependent signaling and Phosphoinositide 3-Kinase (PI3K) expression ( 6 , 7 ).…”