Jeremian Richie, Sivachandran Sriraam, Galati Melissa, Ramchatesingh Brandon, Rijal Hibo, Hanna Johnny, Netchiporouk Elena, Chergui May, Redpath Margaret, Abou Setah Samy, Litvinov Ivan V
Research Institute of the McGill University Health Centre, Montreal, Canada.
Faculty of Medicine, University of Toronto, Canada.
Mol Oncol. 2025 Aug 5. doi: 10.1002/1878-0261.70107.
Merkel cell carcinoma (MCC) is a highly aggressive disease with the poorest prognosis among skin cancers, originally posited to be derived from Merkel cells. Emerging evidence, however, suggests other potential origins for MCC, including hematological lineages. We utilized targeted and multi-omics approaches to explore gene expression patterns at protein and RNA levels of MCCs. Western blotting, immunofluorescence, and immunohistochemistry were performed using fresh and 92 FFPE samples of primary and metastatic MCC, and two MCC cell lines (MS-1, HaCaT). RNA sequencing of selected FFPE samples identified differentially expressed genes based on sex and Merkel cell polyomavirus (MCPyV) status. Finally, weighted gene correlation network analysis (WGCNA) and cell type enrichment analyses were employed to determine pathway and cell type enrichment, respectively. MCC patient samples heterogeneously expressed B-cell and neuroendocrine markers and novel molecular targets including BCMA, CD10, CD93, PAX5, TdT, IgA, and CD19. Transcriptome analysis demonstrated differentially expressed genes based on sex and MCPyV status. MCPyV+ tumors had significant upregulation of genes involved in immune cell function and downregulation of processes related to neuronal activity. WGCNA highlighted enrichment for pathways involved in immune function, including B-cell differentiation. Cell type enrichment analysis highlighted enrichment for multipotent stem cells, several immune cell types, and keratinocytes. Our findings support previous studies which confirm that MCC is unlikely to be derived from Merkel cells and instead from multiple or divergent cell types, including those of B-cell lineage. Our work highlights the need for a more personalized approach to diagnosis/characterization and treatment of MCCs, given the documented variability of novel potentially targetable pathways.
默克尔细胞癌（MCC）是一种侵袭性很强的疾病，在皮肤癌中预后最差，最初认为它起源于默克尔细胞。然而，新出现的证据表明MCC有其他潜在起源，包括血液谱系。我们利用靶向和多组学方法来探索MCC在蛋白质和RNA水平的基因表达模式。使用原发性和转移性MCC的新鲜样本和92个福尔马林固定石蜡包埋（FFPE）样本以及两种MCC细胞系（MS-1、HaCaT）进行了蛋白质免疫印迹、免疫荧光和免疫组织化学实验。对选定的FFPE样本进行RNA测序，根据性别和默克尔细胞多瘤病毒（MCPyV）状态确定差异表达基因。最后，分别采用加权基因共表达网络分析（WGCNA）和细胞类型富集分析来确定通路富集和细胞类型富集情况。MCC患者样本中异质性表达B细胞和神经内分泌标志物以及新的分子靶点，包括B细胞成熟抗原（BCMA）、CD10、CD93、配对盒基因5（PAX5）、末端脱氧核苷酸转移酶（TdT）、免疫球蛋白A（IgA）和CD19。转录组分析显示了基于性别和MCPyV状态的差异表达基因。MCPyV阳性肿瘤中参与免疫细胞功能的基因显著上调，与神经元活动相关的过程下调。WGCNA突出了免疫功能相关通路的富集，包括B细胞分化。细胞类型富集分析突出了多能干细胞、几种免疫细胞类型和角质形成细胞的富集。我们的研究结果支持了之前的研究，这些研究证实MCC不太可能起源于默克尔细胞，而是起源于多种或不同的细胞类型，包括B细胞谱系的细胞类型。鉴于已记录的新型潜在可靶向通路的变异性，我们的工作强调了对MCC进行诊断/特征描述和治疗时需要采用更个性化的方法。
