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 analysed 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<0.05). Conclusion MRE imaging of glioblastoma can provide non-invasive 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.

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, [ 68–70 ] but not gliomas.…”

Tumor biomechanics as a novel imaging biomarker to assess response to immunotherapy in a murine glioma model

“…This heterogeneity was reflected in the histological composition of tumors as areas with high cell density alternated with patchy accumulation of extracellular matrix components as well as with tissue damage presumably caused by necrosis and hemorrhage. The ability to delineate histologically distinct glioma subregions has already been demonstrated in a patient-derived xenograft mouse model of GBM 34 and in patients with glioma 15 . Here, stiff tumor subregions were associated with ECM reorganization and expression patterns of ECM proteins in such stiff tumor areas correlated with a shorter overall survival of patients 15 .…”

“…MRE is sensitive to microstructure and organization of tissue 8 and renders information on brain tumor composition that are complimentary to established MRI parameters 9 – 11 . MRE revealed effects of radiation or anti-angiogenic treatment on glioma stiffness in experimental models 12 , 13 and further studies hint at a relation between extracellular matrix (ECM) stiffening 14 or reorganization 15 and tumor progression. We therefore investigated the effects of myeloid-targeted immunotherapy with CDNP-R848 on biomechanical glioma properties in the syngeneic Gl261 glioma model.…”

A guide to advanced MRI processing for clinical glioma research

“…MRE uniquely and noninvasively tumor stiffness. In glioblastoma, increased stiffness is associated with extracellular matrix reorganization [159]. However, MRE measurements may not agree with the neurosurgeon's stiffness assessment during surgery, suggesting MRE provides independent information about tumor physiology [159].…”

“…In glioblastoma, increased stiffness is associated with extracellular matrix reorganization [159]. However, MRE measurements may not agree with the neurosurgeon's stiffness assessment during surgery, suggesting MRE provides independent information about tumor physiology [159]. The stiffness is quantified by the shear modulus G*, which has both an elastic and a viscous component [160].…”