Metabolic and transcriptomic profiles of glioblastoma invasion revealed by comparisons between patients and corresponding orthotopic xenografts in mice

Abstract

The invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients’ tumors. The evolution of metabolic changes, followed in vivo longitudinally by 1H Magnetic Resonance Spectroscopy (1H MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients’ tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell–cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable for in vivo monitoring of progression in the non-enhancing infiltration zone of glioblastoma.

A pilot study: Metabolic profiling of plasma and saliva samples from newly diagnosed glioblastoma patients

“…While current treatment shows initial efficacy, tumours often recur and develop resistance to treatment. This is in part due to the invasive capacity of GBM, which contributes to the tumour's aggressiveness and resistance to treatment, culminating in high recurrence rates 44 . Post‐treatment surveillance is currently done by MRI but even with optimal imaging, it is difficult to distinguish tumour recurrence from treatment effect 3 .…”

The STEMRI trial: Magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma stem-like cells

“…It has been described that GSC have an increased ability to adhere, migrate, and invade compared to their differentiated counterparts ( 56 , 57 ) but also that those capacities may vary according to the anatomical location of the biopsy, because GSC generated from the GBM peritumoral area displayed a higher migratory and invasive phenotype compared to GSC isolated from the tumor mass ( 58 ). In a recent study associating MRSI and RNA-seq of tumor bulks both in patients with GBM and in paired patient-derived orthotopic xenografts (PDOXs) ( 59 ), it was pointed out (i) that there was a good concordance between metabolite profiles recorded by MRSI in patients and the metabolite profiles observed during PDOX growth and (ii) that this tumor growth and related metabolic profiles (notably high Cho-containing compounds and low NAA), both in human and PDOX, were associated at the molecular level with an enrichment in signatures dedicated to adhesion, invasion and ECM, consistent with our results. All these observations lead us to hypothesize that GSC-enriched NS isolated from FLAIR/CNI+ areas might exhibit higher migratory/invasive and metabolic heterogeneity that could be monitored by at least RNA-seq and MRSI on cells ( 60 ) and in xenografted models ( 29 , 59 ).…”

“…In a recent study associating MRSI and RNA-seq of tumor bulks both in patients with GBM and in paired patient-derived orthotopic xenografts (PDOXs) ( 59 ), it was pointed out (i) that there was a good concordance between metabolite profiles recorded by MRSI in patients and the metabolite profiles observed during PDOX growth and (ii) that this tumor growth and related metabolic profiles (notably high Cho-containing compounds and low NAA), both in human and PDOX, were associated at the molecular level with an enrichment in signatures dedicated to adhesion, invasion and ECM, consistent with our results. All these observations lead us to hypothesize that GSC-enriched NS isolated from FLAIR/CNI+ areas might exhibit higher migratory/invasive and metabolic heterogeneity that could be monitored by at least RNA-seq and MRSI on cells ( 60 ) and in xenografted models ( 29 , 59 ). These results could then be translated and validated at the clinical level through their specific therapeutic targeting to in fine improve radiochemotherapeutic response.…”

The STEMRI trial: magnetic resonance spectroscopy imaging can define tumor areas enriched in glioblastoma-initiating cells

“…Interestingly, it has been described that GSC have an increased ability to adhere, migrate and invade compared to their differentiated counterparts (40,41), but also that those capacities may vary according to the anatomical location of the biopsy, since GIC generated from the GB peritumoral area displayed a higher migratory and invasive phenotype compared to GIC isolated from the tumor mass (42). In a recent study associating MRSI and RNAseq of tumor bulks both in GB patients and in paired patient-derived orthotopic xenografts (PDOX) (43), it was pointed out (i) that there was a good concordance between metabolite profiles recorded by MRSI in patients and the metabolite profiles 16 observed during PDOX growth and (ii) that this tumor growth and related metabolic profiles (notably high choline-containing compounds and low NAA), both in human and PDOX, were associated at the molecular level with an enrichment in signatures dedicated to adhesion, invasion and extracellular matrix, consistent with our results. All these observations lead us to hypothesize that GIC-enriched NS isolated from FLAIR/CNI+ areas might exhibit higher migratory/invasive and metabolic heterogeneity that could be monitored by at least RNAseq and MRSI on cells (44) and in xenografted models (21,43).…”

“…In a recent study associating MRSI and RNAseq of tumor bulks both in GB patients and in paired patient-derived orthotopic xenografts (PDOX) (43), it was pointed out (i) that there was a good concordance between metabolite profiles recorded by MRSI in patients and the metabolite profiles 16 observed during PDOX growth and (ii) that this tumor growth and related metabolic profiles (notably high choline-containing compounds and low NAA), both in human and PDOX, were associated at the molecular level with an enrichment in signatures dedicated to adhesion, invasion and extracellular matrix, consistent with our results. All these observations lead us to hypothesize that GIC-enriched NS isolated from FLAIR/CNI+ areas might exhibit higher migratory/invasive and metabolic heterogeneity that could be monitored by at least RNAseq and MRSI on cells (44) and in xenografted models (21,43). These results could then be translated and validated at the clinical level through their specific therapeutic targeting to in fine improve radiochemotherapeutic response.…”