Xu Da-Ming, Chen Ling-Xiao, Han Hui, Mo Miao
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China.
iScience. 2025 Jan 7;28(2):111765. doi: 10.1016/j.isci.2025.111765. eCollection 2025 Feb 21.
Tumor heterogeneity, driven by branching evolution and genomic mutations, complicates cancer treatment. Understanding malignant cell evolution across various tumors aids in identifying pre-metastatic subpopulations for optimized therapies. Using bulk RNA sequencing (6 primary penile carcinomas, 6 metastatic lymph nodes, GSE196978), single-cell RNA sequencing (4 advanced penile carcinomas), spatial transcriptomics (Squamous cell carcinoma [SCC]: GSE144239-GSM4565823 and SCC: GSE144239-GSM4565826), and cell assays with Silmitasertib, we mapped heterogeneity and pinpointed therapeutic targets. In penile carcinoma, we discovered an MMP3+SPP1+ pre-metastatic subset and casein kinase 2 alpha 1 (CK2α) overexpression. The nuclear factor κB (NF-κB) pathway may drive metastasis. Pan-cancer analysis showed that MMP3 and SPP1 link to epithelial mesenchymal transition (EMT) and drug resistance, while CK2α activates oncogenes. Silmitasertib, a CK2α inhibitor, exhibited anti-tumor effects in penile carcinoma cells. Validated across 98 single-cell and 6 spatial datasets, our study advances the understanding of tumorigenesis and metastasis, highlighting Silmitasertib as a potential therapeutic agent.
由分支进化和基因组突变驱动的肿瘤异质性使癌症治疗变得复杂。了解各种肿瘤中恶性细胞的进化有助于识别转移前亚群，从而优化治疗方案。利用批量RNA测序（6例原发性阴茎癌、6个转移性淋巴结，GSE196978）、单细胞RNA测序（4例晚期阴茎癌）、空间转录组学（鳞状细胞癌[SCC]：GSE144239 - GSM4565823和SCC：GSE144239 - GSM4565826）以及使用西咪替塞替布的细胞试验，我们绘制了异质性图谱并确定了治疗靶点。在阴茎癌中，我们发现了一个MMP3 + SPP1 +转移前亚群以及酪蛋白激酶2α1（CK2α）的过表达。核因子κB（NF - κB）通路可能驱动转移。泛癌分析表明，MMP3和SPP1与上皮间质转化（EMT）和耐药性有关，而CK2α激活致癌基因。西咪替塞替布，一种CK2α抑制剂，在阴茎癌细胞中表现出抗肿瘤作用。通过98个单细胞和6个空间数据集验证，我们的研究推进了对肿瘤发生和转移的理解，突出了西咪替塞替布作为一种潜在治疗药物的作用。
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