Single-cell N6-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy

Abstract

Background N6-methyladenosine (m6A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m6A functions within the tumor microenvironment (TME) remains to be elucidated. Methods A total of 65,362 single cells from single-cell RNA-seq data derived from 33 CRC tumor samples were analyzed by nonnegative matrix factorization (NMF) for 23 m6A RNA methylation regulators. CRC and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of TME clusters. Results The fibroblasts, macrophages, T and B cells were respectively grouped into 4 to 5 subclusters and then classified according to various biological processes and different marker genes. Furthermore, it revealed that the m6A RNA methylation regulators might be significantly related to the clinical and biological features of CRC, as well as the pseudotime trajectories of main TME cell types. Bulk-seq analysis suggested that these m6A-mediated TME cell subclusters had significant prognostic value for CRC patients and distinguished immune response for patients who underwent ICB therapy, especially for the CAFs and macrophages. Notably, CellChat analysis revealed that RNA m6A methylation-associated cell subtypes of TME cells manifested diverse and extensive interaction with tumor epithelial cells. Further analysis showed that ligand-receptor pairs, including MIF − (CD74 + CXCR4), MIF − (CD74 + CD44), MDK–NCL and LGALS9 − CD45, etc. mediated the communication between m6A associated subtypes of TME cells and tumor epithelial cells. Conclusions Taken together, our study firstly revealed the m6A methylation mediated intercellular communication of the tumor microenvironment in the regulation of tumor growth and antitumor immunomodulatory processes.

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Research progress of traditional Chinese medicine as sensitizer in reversing chemoresistance of colorectal cancer

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Single‐cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy

“…4.2.7 | The functional and phenotype inference of DDR-related cell subtypes ssGSEA was performed using the GSVA algorithm. The AddModuleScore was used to evaluate the CAF phenotype subtypes (Guo et al, 2018)， CD8+ T cell function signatures as previously described (Guo et al, 2018) including a validated panel of 90 exhaustion-associated genes, and 12 cytotoxicity-associated genes, and M1/M2 polarization scores (Gao et al, 2022). The metabolic activation state was evaluated by the scMetabolism package.…”