Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia.
J Thorac Oncol. 2022 Dec;17(12):1375-1386. doi: 10.1016/j.jtho.2022.08.008. Epub 2022 Aug 30.
The pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear.
To investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors.
We observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas.
We have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies.
胸腺癌的发病机制仍知之甚少。我们之前发现 GTF2I L424H 是胸腺癌中最常发生的突变。然而，这种突变在胸上皮细胞肿瘤发生中的精确作用尚不清楚。
为了研究 GTF2I L424H 突变在胸上皮细胞中的作用，我们构建并鉴定了一个条件性敲入 Foxn1+ 胸上皮细胞 Gtf2i L424H 突变的小鼠模型。利用 GeoMx-mouse 全转录组图谱对胸腺瘤和正常胸腺组织进行数字空间分析。利用小鼠组织和人类胸腺癌进行免疫组织化学染色。
我们观察到 Gtf2i 突变可损害年轻小鼠的胸腺皮质发育和皮质胸腺上皮细胞的成熟，并导致老年小鼠胸腺肿瘤的形成。细胞周期相关通路，如 E2F 靶点和 MYC 靶点，在肿瘤上皮细胞中富集。基因集变异分析结果表明，皮质胸腺上皮细胞和胸腺上皮祖细胞的基因特征也在敲入小鼠的胸腺瘤中富集，这与 The Cancer Genome Atlas 数据库中的人类胸腺瘤相对应。免疫组织化学结果显示，小鼠和人类胸腺瘤的上皮细胞标志物表达模式相似。
我们已经开发并鉴定了一种新型胸腺瘤小鼠模型。这项研究提高了对胸上皮细胞中分子驱动因素的认识，并为进一步研究胸上皮肿瘤的生物学和开发新的治疗方法提供了工具。
