Abstract
Background
The involvement of ferroptosis in the pathogenesis and progression of various cancers has been well established. However, limited studies have investigated the role of ferroptosis-mediated tumor microenvironment (TME) in skin cutaneous melanoma (SKCM).
Methods
By leveraging single-cell RNA sequencing data, the nonnegative matrix factorization (NMF) approach was employed to comprehensively characterize and identify distinct gene signatures within ferroptosis-associated TME cell clusters. Prognostic and treatment response analyses were conducted using both bulk datasets and external cancer cohort to evaluate the clinical implications of TME clusters.
Results
This NMF-based analysis successfully delineated fibroblasts, macrophages, T cells, and B cells into multiple clusters, enabling the identification of unique gene expression patterns and the annotation of distinct TME clusters. Furthermore, pseudotime trajectories, enrichment analysis, cellular communication analysis, and gene regulatory network analysis collectively demonstrated significant intercellular communication between key TME cell clusters, thereby influencing tumor cell development through diverse mechanisms. Importantly, our bulk RNA-seq analysis revealed the prognostic significance of ferroptosis-mediated TME cell clusters in SKCM patients. Moreover, our analysis of immune checkpoint blockade highlighted the crucial role of TME cell clusters in tumor immunotherapy, facilitating the discovery of potential immunotherapeutic targets.
Conclusions
In conclusion, this pioneering study employing NMF-based analysis unravels the intricate cellular communication mediated by ferroptosis within the TME and its profound implications for the pathogenesis and progression of SKCM. We provide compelling evidence for the prognostic value of ferroptosis-regulated TME cell clusters in SKCM, as well as their potential as targets for immunotherapy.
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Data availability
Publicly available datasets were analyzed in this study. These data can be found here: The datasets analyzed in the current study are available in the GEO and TCGA database. All raw data and original images can be found in the jianguoyun (https://www.jianguoyun.com/p/DYLfxGkQjpbCCxit5JAFIAA).
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This study was funded by the National Natural Science Foundation of China (82072182, 82002061).
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BYS, YZ, and YP conceptualized and designed the study; BYS, WL, and YZ contributed to data curation and methodology; BYS, YP, KW, and ZC analyzed and interpreted the data; BYS wrote the manuscript; and BQS reviewed the manuscript and took part in study supervision. All authors read and approved the final manuscript.
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Supplemental Figure 1 A–I Results of K–M survival analysis of NMF cells clusters in the external dataset of bladder cancer. The survival analysis of each high and low NMF cell cluster grouping in bladder cancer was significantly different (p < 0.05) (PDF 514 kb)
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Song, B., Peng, Y., Zheng, Y. et al. Role of single-cell ferroptosis regulation in intercellular communication and skin cutaneous melanoma progression and immunotherapy. Cancer Immunol Immunother 72, 3523–3541 (2023). https://doi.org/10.1007/s00262-023-03504-5
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DOI: https://doi.org/10.1007/s00262-023-03504-5