Introduction Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with “neuroendocrine (NE)-low” cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell–derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. Methods YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. Results RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. Conclusions YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.

中文翻译：

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在 39 个循环肿瘤细胞患者衍生的外植体模型 (CDX) 的生物库中重新审视了罕见的小细胞肺癌 YAP1 亚型：简要报告

简介 最近的共识根据转录因子表达定义了四种 SCLC 亚型：ASCL1、NEUROD1、POU2F3 和 YAP1。罕见的 YAP1 亚型与 SCLC 细胞系和患者样本中的“神经内分泌 (NE)-l​​ow”细胞有关。我们在 39 名具有不同表型循环肿瘤细胞衍生外植体 (CDX) 模型的患者中评估了 YAP1，并在患病率、细胞表型以及肿瘤间和肿瘤内异质性方面重新审视了 YAP1。方法 YAP1 转录物和蛋白表达通过 NE 和非 NE CDX 亚群的 RNA 测序和免疫组织化学或多重免疫荧光评估。对于 YAP1、NE 标记 SYP 和 AXL，对物理分离的 NE 和非 NE CDX 离体培养裂解物进行了西方印迹。结果 对四种亚型转录因子进行标准化的 RNA 测序在 39 个 CDX 中的 14 个中确定了 YAP1 的表达。共有 10 个 CDX 表达 YAP1 蛋白，其中 8 个具有强 YAP1 表达，仅限于罕见的非 NE 细胞簇。这在离体 CDX 培养物中得到证实，其中缺乏 SYP 表达的贴壁非 NE 细胞表达 YAP1。然而，在两个 CDX 中，观察到较弱的细胞 YAP1 表达，广泛分散在 SYP 阳性 NE 细胞中。结论 YAP1主要在SCLC CDX的非NE细胞簇中表达，但39个CDX中有两个在NE细胞中表达YAP1。CDX22P 具有相对较高的 YAP1 表达，是一种 ASCL1 NE 亚型，具有低 NE 评分，并且在我们的 CDX 生物库中该亚型中的异常值。这些描述性数据揭示了细微不同的 YAP1 表达谱，