Dataset Information

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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC9066909 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Single-cell N<sup>6</sup>-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy.

Gao Yuzhen Y Wang Hao H Chen Shipeng S An Rui R Chu Yadong Y Li Guoli G Wang Yanzhong Y Xie Xinyou X Zhang Jun J

Journal of translational medicine 20220504 1

<h4>Background</h4>N6-methyladenosine (m<sup>6</sup>A) RNA methylation plays a critical role in key genetic events for various cancers; yet, how m<sup>6</sup>A functions within the tumor microenvironment (TME) remains to be elucidated.<h4>Methods</h4>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 m<sup>6</sup>A RNA methylation regulators. CRC and Immunotherapy cohorts from public reposi ...[more]

PMID: 35509079

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Project description:BackgroundDisulfidptosis, an emerging type of programmed cell death, plays a pivotal role in various cancer types, notably impacting the progression of kidney renal clear cell carcinoma (KIRC) through the tumor microenvironment (TME). However, the specific involvement of disulfidptosis within the TME remains elusive.MethodsAnalyzing 41,784 single cells obtained from seven samples of KIRC through single-cell RNA sequencing (scRNA-seq), this study employed nonnegative matrix factorization (NMF) to assess 24 disulfidptosis regulators. Pseudotime analysis, intercellular communication mapping, determination of transcription factor activities (TFs), and metabolic profiling of the TME subgroup in KIRC were conducted using Monocle, CellChat, SCENIC, and scMetabolism. Additionally, public cohorts were utilized to predict prognosis and immune responses within the TME subgroup of KIRC.ResultsThrough NMF clustering and differential expression marker genes, fibroblasts, macrophages, monocytes, T cells, and B cells were categorized into four to six distinct subgroups. Furthermore, this investigation revealed the correlation between disulfidptosis regulatory factors and the biological traits, as well as the pseudotime trajectories of TME subgroups. Notably, disulfidptosis-mediated TME subgroups (DSTN+CD4T-C1 and FLNA+CD4T-C2) demonstrated significant prognostic value and immune responses in patients with KIRC. Multiple immunohistochemistry (mIHC) assays identified marker expression within both cell clusters. Moreover, CellChat analysis unveiled diverse and extensive interactions between disulfidptosis-mediated TME subgroups and tumor epithelial cells, highlighting the TNFSF12-TNFRSF12A ligand-receptor pair as mediators between DSTN+CD4T-C1, FLNA+CD4T-C2, and epithelial cells.ConclusionOur study sheds light on the role of disulfidptosis-mediated intercellular communication in regulating the biological characteristics of the TME. These findings offer valuable insights for patients with KIRC, potentially guiding personalized immunotherapy approaches.

Project description:ObjectiveGastroesophageal adenocarcinoma (GEA) is a high deadly and heterogeneous cancer. RNA N6-methyladenosine (m6A) modification plays a non-negligible role in shaping individual tumour microenvironment (TME) characterizations. However, the landscape and relationship of m6A modification patterns and TME cell infiltration features remain unknown in GEA.MethodsIn this study, we examined the TME of GEA using assessments of the RNA-sequencing data focusing on the distinct m6A modification patterns from the public databases. Intrinsic patterns of m6A modification were evaluated for associations with clinicopathological characteristics, underlying biological pathways, tumour immune cell infiltration, oncological outcomes, and treatment responses. The expression of key m6A regulators and module genes was validated by qRT-PCR analysis.ResultsWe identified two distinct m6A modification patterns of GEA (cluster 1/2 subgroup), and correlated two subgroups with TME cell-infiltrating characteristics. Cluster 2 subgroup correlates with a poorer prognosis, downregulated PD-1 expression, higher risk scores, and distinct immune cell infiltration. In addition, PPI and WGCNA network analysis were integrated to identify key module genes closely related to immune infiltration of GEA to find immunotherapy markers. COL4A1 and COL5A2 in the brown module were significantly correlated to the prognosis, PD-1/L1 and CTLA-4 expression of GEA patients. Finally, a prognostic risk score was constructed using m6A regulator-associated signatures that represented an independent prognosis factor for GEA. Interestingly, COL5A2 expression was linked to the response to anti-PD-1 immunotherapy, m6A regulator expression, and risk score.ConclusionOur work identified m6A RNA methylation regulators as an important class of players in the malignant progression of GEA and were associated with the complexity of the TME. COL5A2 may be the potential biomarker which contributes to predicting the response to anti-PD-1 immunotherapy and patients' prognosis.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Single-cell N<sup>6</sup>-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

Single-cell N<sup>6</sup>-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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