Background: The histogenesis of thymic epithelial tumors (TETs) has been a subject of debate. Recent technological advancements have revealed that thymic carcinomas often exhibit a phenotype akin to tuft cells, which is a subset of medullary TECs. Here, we further explored the gene expression signatures of thymic carcinomas in relation to tuft cells and their kinships—ionocytes and neuroendocrine cells (neuroendocrine group). Methods: We analyzed a single-cell RNA sequencing dataset from the normal human thymus. Concurrently, we examined publicly available datasets on the mRNA expression and methylation status of TECs and lung cancers. Real-time quantitative PCR was also conducted with our tissue samples. Results: Thymic carcinomas displayed a neuroendocrine phenotype biased toward tuft cells and ionocytes. When exploring the possible regulators of this phenotype, we discovered thatHDAC9andNFATC1were characteristically expressed in the neuroendocrine group in adult TECs and thymic carcinomas. Additionally, the pan-thymic epithelium markers, exemplified byPAX9andSIX1, were significantly suppressed in thymic carcinomas. Conclusions: Thymic carcinomas might be characterized by unique neuroendocrine differentiation and loss of identity as thymic epithelial cells. Future studies investigating the role of HDAC9 and NFATC1 in thymic epithelium are warranted to explore their potential as therapeutic targets in TETs.
背景：胸腺上皮肿瘤（TETs）的组织发生一直存在争议。近期技术进展显示，胸腺癌常表现出类似簇细胞（髓质胸腺上皮细胞的一个亚群）的表型。本研究进一步探讨了胸腺癌与簇细胞及其相关细胞类型——离子细胞和神经内分泌细胞（神经内分泌组群）的基因表达特征。方法：我们分析了正常人胸腺的单细胞RNA测序数据集，同时考察了公开可用的胸腺上皮细胞和肺癌mRNA表达及甲基化状态数据集，并利用本课题组组织样本进行了实时定量PCR验证。结果：胸腺癌表现出偏向簇细胞和离子细胞的神经内分泌表型。在探索该表型的潜在调控因子时，我们发现HDAC9和NFATC1在成人胸腺上皮细胞及胸腺癌的神经内分泌组群中具有特征性表达。此外，以PAX9和SIX1为代表的泛胸腺上皮标志物在胸腺癌中显著抑制。结论：胸腺癌可能具有独特的神经内分泌分化特征，并丧失了胸腺上皮细胞的身份特性。未来需要深入研究HDAC9和NFATC1在胸腺上皮中的作用，以探索其作为TETs治疗靶点的潜力。
Thymic Carcinoma: Unraveling Neuroendocrine Differentiation and Epithelial Cell Identity Loss
肿瘤(癌症)患者之家