MR elastography identifies regions of extracellular matrix reorganization associated with shorter survival in glioblastoma patients

Abstract

Background

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 classified as “stiff” or “soft” according to MRE stiffness measurements (|G*|norm). Twenty-two biopsies from eight patients were analyzed by RNA sequencing. Results

The mean whole-tumor stiffness was lower than normal-appearing white matter. The surgeon’s stiffness evaluation did not correlate with the MRE measurements, which suggests that these measures assess different physiological properties. Pathway 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 glioblastoma patients were divided into those with (n = 63) and without (n = 202) this gene expression signal. The median survival time of patients with tumors expressing the gene 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 < .05). Conclusion

MRE imaging of glioblastoma can provide noninvasive information on intratumoral heterogeneity. Regions of increased stiffness were associated with extracellular matrix reorganization. An expression signal associated with “stiff” biopsies correlated with shorter survival of glioblastoma patients.