MOMC-4. Proteogenomic and metabolomic characterization of glioblastoma

Abstract

Glioblastoma (GBM) is the most aggressive nervous system cancer, with median survival under 2 years. Understanding its molecular pathogenesis is crucial for improving diagnosis and treatment. We performed an integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs. We identified key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation as well as potential targets for EGFR-, TP53- and RB1-altered tumors. We detected immune subtypes, driven by the presence of distinct immune cell populations using bulk omics, validated by single nulcei RNA sequencing (snRNA-seq), and they were correlated with specific expression and histone acetylation patterns. Acetylation of histone H2B in classical-like and immune-low GBM was driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identified specific lipid distributions across subtypes and distinct global metabolic changes in IDH mutated tumors. This work highlights biological relationships which could potentially aid GBM patient stratifications for more effective treatments.

The SVZ stem cell niche–components, functions, and in vitro modelling

“…It has been shown that glioblastoma contain a proliferative cell population that shares a similar transcriptional signature with bRG. These bRG-like cells express certain bRG markers that mediate ECM interactions, and display bRG-like morphology, which could promote the expansion and the invasiveness of glioblastoma tumors (Bhaduri et al, 2020;Wang et al, 2021). This suggests that a similar niche that supports bRG proliferation could be acquired in glioblastoma to provide a microenvironment permissive for tumor expansion.…”

Variant biomarker discovery using mass spectrometry-based proteogenomics

“…The group identified protein and genetic signatures in these subtypes strongly tied to age, gender, and EGFR-mutation status, contributing important considerations for the development of disease-modifying therapies. Furthermore, integrated analyses of multi-omics data from glioblastoma (GBM) samples unveiled new immune-based subtypes, expanding on previous classifications based only on transcriptomic and genomic data (Wang et al, 2017;Wang et al, 2021). Notably, the study subdivided glioblastoma into two distinct groups, allowing for future, more in-depth mechanistic studies to reveal therapeutic vulnerabilities in these newly discovered subclasses for precision medicine (Oh et al, 2020).…”

WNT signaling at the intersection between neurogenesis and brain tumorigenesis

“…About 90% of GBM cases exhibit an altered p53/cell cycle arrest/apoptosis pathway (Wang et al, 2021), and frequent dysfunctions in oncogenic pathways have been reported in GBM. EGFR is amplified and hyperactive in about 60% of GBM patients (Lee et al, 2016).…”

“…This amplification disrupts the downstream signaling. Hence, 63% and 86% of GBM patients have altered RTK/PI3K pathway and RTK/MAPK pathway, respectively (Wang et al, 2021). These molecular alterations contribute to the increased capacity of tumor cells to proliferate, survive, migrate and invade healthy brain tissue (Daisy Precilla et al, 2022).…”