Comprehensive data mining reveals RTK/RAS signaling pathway as a promoter of prostate cancer lineage plasticity through transcription factors and CNV

• Published in: Scientific reports 2024-05, Vol.14 (1), p.11688-11688, Article 11688
• Main Authors: Wei, Guanyun, Zhang, Xu, Liu, Siyuan, Hou, Wanxin, Dai, Zao
• Format: Article
• Language: English
• Subjects: 631/114/2164; 631/114/2401; 692/4028/67; 692/4028/67/589/466; Cell Lineage - genetics; Copy number; Data Mining; DNA Copy Number Variations; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; FOXO1 protein; Gene Expression Regulation, Neoplastic; Gene regulation; Gene Regulatory Networks; Genes; Humanities and Social Sciences; Humans; Male; multidisciplinary; Plasticity; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; ras Proteins - genetics; ras Proteins - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-62256-z

Prostate cancer lineage plasticity is a key driver in the transition to neuroendocrine prostate cancer (NEPC), and the RTK/RAS signaling pathway is a well-established cancer pathway. Nevertheless, the comprehensive link between the RTK/RAS signaling pathway and lineage plasticity has received limited investigation. In particular, the intricate regulatory network governing the interplay between RTK/RAS and lineage plasticity remains largely unexplored. The multi-omics data were clustered with the coefficient of argument and neighbor joining algorithm. Subsequently, the clustered results were analyzed utilizing the GSEA, gene sets related to stemness, multi-lineage state datasets, and canonical cancer pathway gene sets. Finally, a comprehensive exploration of the data based on the ssGSEA, WGCNA, GSEA, VIPER, prostate cancer scRNA-seq data, and the GPSAdb database was conducted. Among the six modules in the clustering results, there are 300 overlapping genes, including 3 previously unreported prostate cancer genes that were validated to be upregulated in prostate cancer through RT-qPCR. Function Module 6 shows a positive correlation with prostate cancer cell stemness, multi-lineage states, and the RTK/RAS signaling pathway. Additionally, the 19 leading-edge genes of the RTK/RAS signaling pathway promote prostate cancer lineage plasticity through a complex network of transcriptional regulation and copy number variations. In the transcriptional regulation network, TP63 and FOXO1 act as suppressors of prostate cancer lineage plasticity, whereas RORC exerts a promoting effect. This study provides a comprehensive perspective on the role of the RTK/RAS pathway in prostate cancer lineage plasticity and offers new clues for the treatment of NEPC.