Defining the first bona fide cell model for SMARCA4‐deficient, undifferentiated tumor

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.