PDF(Pubmed)
Abstract：
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.
摘要：
前列腺癌谱系可塑性是向神经内分泌前列腺癌（NEPC）过渡的关键驱动因素，和RTK/RAS信号通路是一个成熟的癌症通路。然而，RTK/RAS信号通路与谱系可塑性之间的综合联系受到了有限的研究.特别是,控制RTK/RAS和谱系可塑性之间相互作用的复杂监管网络在很大程度上仍未被探索。采用自变量系数和邻居连接算法对多组数据进行聚类。随后，利用GSEA对聚类结果进行了分析，与干性相关的基因集，多谱系状态数据集，和典型的癌症通路基因集。最后,基于ssGSEA的数据的全面探索，WGCNA,GSEA,VIPER,前列腺癌scRNA-seq数据，并进行了GPSAdb数据库。在聚类结果的六个模块中，有300个重叠的基因，包括3个以前未报告的前列腺癌基因，这些基因通过RT-qPCR验证在前列腺癌中上调。功能模块6显示与前列腺癌细胞干细胞呈正相关,多谱系状态，和RTK/RAS信号通路。此外,RTK/RAS信号通路的19个前沿基因通过转录调控和拷贝数变异的复杂网络促进前列腺癌谱系可塑性.在转录调控网络中，TP63和FOXO1作为前列腺癌谱系可塑性的抑制剂，而RORC发挥促进作用。本研究为RTK/RAS通路在前列腺癌谱系可塑性中的作用提供了全面的视角，并为NEPC的治疗提供了新的线索。
