Abstract：
The World Health Organization\'s tumor classification guidelines are frequently updated and renewed as knowledge of cancer biology advances. For instance, in 2021, a novel lung tumor subtype named SMARCA4-deficient, undifferentiated tumor (SMARCA4-dUT, code 8044/3) was included. To date, there is no defined cell model for SMARCA4-dUT that could be used to help thoracic clinicians and researchers in the study of this newly defined tumor type. As this tumor type was recently described, it is feasible that some cell models formerly classified as lung adenocarcinoma (LUAD) could now be better classified as SMARCA4-dUT. Thus, in this work, we aimed to identify a bona fide cell model for the experimental study of SMARCA4-dUT. We compared the differential expression profiles of 36 LUAD-annotated cell lines and 38 cell lines defined as rhabdoid in repositories. These comparative results were integrated with the mutation and expression profiles of the SWI/SNF complex members, and they were surveyed for the presence of the SMARCA4-dUT markers SOX2, SALL4, and CD34, measured by RT-qPCR and western blotting. Finally, the cell line with the paradigmatic SMARCA4-dUT markers was engrafted into immunocompromised mice to assess the histological morphology of the formed tumors and compare them with those formed by a bona fide LUAD cancer cell line. NCI-H522, formerly classified as LUAD, displayed expression profiles nearer to rhabdoid tumors than LUAD tumors. Furthermore, NCI-H522 has most of the paradigmatic features of SMARCA4-dUT: hemizygous inactivating mutation of SMARCA4, severe SMARCA2 downregulation, and high-level expression of stem cell markers SOX2 and SALL4. In addition, the engrafted tumors of NCI-H522 did not display a typical differentiated glandular structure as other bona fide LUAD cell lines (A549) do but had rather a largely undifferentiated morphology, characteristic of SMARCA4-dUT. Thus, we propose the NCI-H522 as the first bona fide cell line model of SMARCA4-dUT. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
随着癌症生物学知识的进步，世界卫生组织的肿瘤分类指南经常更新和更新。例如,2021年，一种名为SMARCA4缺陷型的新型肺肿瘤亚型，未分化肿瘤（SMARCA4-dUT，代码8044/3)被包括在内。迄今为止,SMARCA4-dUT没有明确的细胞模型可用于帮助胸部临床医生和研究人员研究这种新定义的肿瘤类型.正如最近描述的这种肿瘤类型，一些以前分类为肺腺癌(LUAD)的细胞模型现在可以更好地分类为SMARCA4-dUT是可行的.因此，在这项工作中，我们旨在为SMARCA4-dUT的实验研究确定一个真正的细胞模型。我们比较了存储库中36个LUAD注释的细胞系和38个定义为横纹肌的细胞系的差异表达谱。这些比较结果与SWI/SNF复合物成员的突变和表达谱相结合，并通过RT-qPCR和蛋白质印迹法测量了SMARCA4-dUT标记物SOX2，SALL4和CD34的存在。最后,将具有典型SMARCA4-dUT标记的细胞系移植到免疫功能低下的小鼠中,以评估形成的肿瘤的组织学形态,并将其与真正的LUAD癌细胞系形成的肿瘤进行比较.NCI-H522，以前被归类为LUAD，显示的表达谱比LUAD肿瘤更接近横纹肌样肿瘤。此外，NCI-H522具有SMARCA4-dUT的大多数典型特征：SMARCA4的半合子失活突变，严重的SMARCA2下调，干细胞标志物SOX2和SALL4的高水平表达。此外,NCI-H522的移植肿瘤不像其他真正的LUAD细胞系（A549）那样表现出典型的分化腺体结构，但具有很大程度上未分化的形态。SMARCA4-dUT的特性。因此，我们提出NCI-H522作为SMARCA4-dUT的第一个真正的细胞系模型。©2023作者。由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
