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BackgroundMerkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable, and the expression profile of MCC tumors is, to our knowledge, unexplored.MethodsHere, we leveraged bulk and single-cell RNA-Seq of patient-derived tumor biopsies and cell lines to explore the underlying transcriptional environment of MCC.ResultsStrikingly, MCC samples could be separated into transcriptional subtypes that were independent of MCPyV status. Instead, we observed an inverse correlation between a NE gene signature and the Hippo pathway transcription factors Yes1-associated transcriptional regulator (YAP1) and WW domain-containing transcriptional regulator 1 (WWTR1). This inverse correlation was broadly present at the transcript and protein levels in the tumor biopsies as well as in established and patient-derived cell lines. Mechanistically, expression of YAP1 or WWTR1 in a MCPyV-positive MCC cell line induced cell-cycle arrest at least in part through TEA domain-dependent (TEAD-dependent) transcriptional repression of MCPyV LT.ConclusionThese findings identify what we believe to be a previously unrecognized heterogeneity in NE gene expression within MCC and support a model of YAP1/WWTR1 silencing as essential for the development of MCPyV-positive MCC.FundingUS Public Health Service grants R35CA232128, P01CA203655, and P30CA06516.

背景

Merkel 细胞癌（MCC）是一种侵袭性神经内分泌（NE）皮肤癌，由严重的紫外线诱导突变或 Merkel 细胞多瘤病毒（MCPyV）大、小 T 抗原（LT 和 ST）的表达引起。尽管 MCPyV 阳性和阴性亚型之间存在深刻的遗传差异，但目前的临床诊断标志物无法区分，而且据我们所知，MCC 肿瘤的表达谱尚未得到探索。

方法

在这里，我们利用患者来源的肿瘤活检和细胞系的批量和单细胞 RNA-Seq 来探索 MCC 的潜在转录环境。

结果

令人惊讶的是，MCC 样本可以根据转录亚型进行分离，而与 MCPyV 状态无关。相反，我们观察到 NE 基因特征与 Hippo 通路转录因子 Yes1 相关转录调节剂（YAP1）和 WW 结构域包含转录调节剂 1（WWTR1）之间呈反比关系。这种反比关系在肿瘤活检以及已建立和患者来源的细胞系中在转录和蛋白水平上广泛存在。从机制上讲，在 MCPyV 阳性 MCC 细胞系中表达 YAP1 或 WWTR1 至少部分通过 TEA 结构域依赖性（TEAD 依赖性）转录抑制 MCPyV LT 诱导细胞周期停滞。