RNA modification patterns based on major RNA modifications define tumor microenvironment characteristics in glioblastoma

Abstract

RNA modifications play a major role in tumorigenicity and progression, but the expression and function in glioblastoma (GBM) have not been well described. In this study, we developed a GBM score based on the differentially expressed genes (DEGs) between groups showing RNA modification patterns. We assessed the association between the GBM score and tumor microenvironment (TME) characteristics. Based on the gene expression of these regulators, we identified two clusters with distinct RNA modification patterns. Kaplan–Meier survival curves showed that patients in cluster 1 had worse survival than those in cluster 2. Kaplan–Meier and multivariate Cox regression analyses showed that GBM scores (based on DEGs between RNA modification patterns) are an independent predictive biomarker for patient prognosis. Besides, we found that samples with high scores were significantly associated with epithelial-to-mesenchymal transition and immune checkpoints, while samples with low scores were associated with cell cycle regulation. Importantly, GBM-score markedly positively correlated drug resistance, while negatively correlated with drug sensitive. The responders of anti-PD-1/PD-L1 immunotherapy tend to have a lower GBM score than non-responders. In conclusion, our comprehensive analysis of multiple RNA modifications in GBM revealed that RNA modification regulators were closely correlated with TME.

miRNome and Proteome Profiling of Small Extracellular Vesicles Secreted by Human Glioblastoma Cell Lines and Primary Cancer Stem Cells

“…mRNA modifications also appear to have functional roles in glioblastoma in controlling the expression of oncogenes and tumor suppressors [ 78 , 79 ]. Moreover, genomic studies revealed that the expression levels of selected RNA modification enzymes define the tumor microenvironment in glioblastoma [ 80 ]. We hypothesize that RNA modification enzymes retrieved in CSC-sEVs could promote preferential decoding of specific sets of genes to support stress response and survival.…”

Hypoxia regulates tumour characteristic RNA modifications in ovarian cancers

“…Previous database-based studies have suggested that the levels of six RNA modifications (m1A, m5C, m6A, m6Am, m7G and Ψ), including m6A, in pharmacogene RNA may influence drug treatment efficacy [31]. It has also been reported that expression profiles of RNA modification writers in glioblastoma, colorectal cancer and lung cancer can stratify cancer patients and predict treatment response to chemotherapy or immunotherapy with immune checkpoint inhibitors [17,18,32], but the actual RNA modification levels have not been validated. We found, for the first time, that RNA modifications can predict cancer grade and drug response.…”

The epitranscriptome of high-grade gliomas: a promising therapeutic target with implications from the tumor microenvironment to endogenous retroviruses

“…A recent study by Li and colleagues recognized this. It developed a GBM score’ based on the differentially expressed genes (DEGs) between groups showing RNA modification patterns of writers that catalyze m1A methylation, m6A methylation, APA, and A-to-I RNA editing [ 46 ]. Out of the 26 writers analyzed, 15 were found to be more highly expressed in tumor tissue than adjacent normal tissue.…”

“…The immunosuppressive tumor microenvironment has been identified as the primary reason for the failure of immune therapy in GBM patients; currently, there are no FDA-approved immunotherapies for GBM [ 47 ]. Accumulating evidence has shown a strong correlation between RNA modifications, namely m6A, and immunomodulation, and thus the efficacy of immunotherapies in GBM patients [ 43 , 46 , 48 – 50 ]. This correlation does not appear to be unique to primary brain tumors, as similar data has been found in colorectal cancer [ 51 ], colon cancer [ 52 ], gastric cancer [ 42 ], bladder cancer [ 53 ], lung adenocarcinoma [ 54 ], and head and neck squamous cell carcinoma [ 55 ].…”