MRI Elastography Identifies Regions of Extracellular Matrix Reorganization Associated with Shorter Survival in Glioblastoma Patients

Abstract

Background: The biomechanical tissue properties of glioblastoma tumors are heterogeneous, but the molecular mechanisms involved and the biological implications are poorly understood. Here, we combine magnetic resonance elastography (MRE) measurement of tissue stiffness with RNA sequencing of tissue biopsies to explore the molecular characteristics of the stiffness signal. Methods: MRE was performed preoperatively in 13 patients with glioblastoma. Navigated biopsies were harvested during surgery and later classified as ′stiff′ or ′soft′ according to MRE stiffness measurements (|G*|norm). Twenty-two biopsies from eight patients were analysed by RNA sequencing. Results: The mean whole-tumor stiffness was lower than in normal-appearing white matter. The surgeon′s biopsy stiffness evaluation did not correlate with the MRE measurements, which suggests that they measure different properties. Gene set enrichment analysis of the differentially expressed genes between ′stiff′ and ′soft′ biopsies showed that genes involved in extracellular matrix reorganization and cellular adhesion were overexpressed in ′stiff′ biopsies. Supervised dimensionality reduction identified a gene expression signal separating ′stiff′ and ′soft′ biopsies. Using the NIH Genomic Data Portal, 265 patients with glioblastoma were divided into patients with (n=63) and without (n=202) this gene expression signal. The median survival time of patients with tumors expressing the gene expression signal associated with ′stiff′ biopsies was 100 days shorter than that of patients not expressing it (360 versus 460 days, hazard ratio: 1.45, P<0.05). Conclusion: MRE imaging of glioblastoma can provide non-invasive information on intratumoral heterogeneity. Regions of extracellular matrix reorganization showed an expression signal correlated to shorter survival time in patients with glioblastoma.

Unveiling the Influence of Tumor Microenvironment and Spatial Heterogeneity on Temozolomide Resistance in Glioblastoma Using an Advanced Human In Vitro Model of the Blood‐Brain Barrier and Glioblastoma

“…[65] GOLGA4 is not well known to be involved in tumorigenesis, although fusions to RAF1 have been observed in some cancers, [66] and a correlation to stiff extracellular matrices in glioblastoma that negatively correlates to prognosis was identified. [67] KCTD12 (Potassium Channel Tetramerization Domain Containing 12) was also enriched in GPC+BBB microtissues (Figure 6A,B), and is involved in GABA B2 receptor signaling, Wnt-Notch signaling, and G2/M transition. [68] KCTD12 has also been implicated in other cancers, [68][69][70] but not gliomas.…”