Mokkapati Sharada, Manyam Ganiraju, Steinmetz Alexis R, Tholomier Côme, Martini Alberto, Choi Woonyoung, Czerniak Bogdon, Lee Byron H, Dinney Colin P, McConkey David J
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Transl Oncol. 2025 Feb;52:102269. doi: 10.1016/j.tranon.2024.102269. Epub 2025 Jan 13.
Bladder cancer (BLCA) genomic profiling has identified molecular subtypes with distinct clinical characteristics and variable sensitivities to frontline therapy. BLCAs can be categorized into luminal or basal subtypes based on their gene expression. We comprehensively characterized nine human BLCA cell lines (UC3, UC6, UC9, UC13, UC14, T24, SCaBER, RT4V6 and RT112) into molecular subtypes using orthotopic xenograft models. Patient-derived, luciferase-tagged BLCA cell lines were cultured in vitro and engrafted into bladders of NSG mice. Tumor growth was monitored using bioluminescence imaging and mRNA-based molecular classification was used to characterize xenografts into molecular subtypes. RNAseq analysis and basal, luminal, and epithelial-mesenchymal transition (EMT) marker expression revealed distinct patterns; certain cell lines expressed predominantly basal or luminal markers while others demonstrated mixed expression. SCaBER expressed high basal and EMT markers and low luminal markers, consistent with a true basal cell. RT4V6 was a true luminal cell line, displaying only high luminal makers. UC13, T24 and UC3 only showed increased expression of EMT markers. RT112, UC6, UC9 and UC14 expressed basal, luminal, and EMT markers. Immunohistochemical analysis validated our findings. Ki67 was assessed as a continuous percentage of positively stained cells. Morphological assessment of xenografts included H&E and α-SMA staining. These findings will allow for the rational use of appropriate models to develop targeted therapies to overcome or manipulate mechanisms of treatment resistance in BLCA.
膀胱癌（BLCA）的基因组分析已确定了具有不同临床特征和对一线治疗敏感性各异的分子亚型。根据基因表达情况，BLCA可分为腔面型或基底型亚型。我们使用原位异种移植模型，全面地将九种人类BLCA细胞系（UC3、UC6、UC9、UC13、UC14、T24、SCaBER、RT4V6和RT112）鉴定为分子亚型。将患者来源的、带有荧光素酶标签的BLCA细胞系在体外培养，然后植入NSG小鼠的膀胱。使用生物发光成像监测肿瘤生长，并基于mRNA的分子分类法将异种移植瘤鉴定为分子亚型。RNA测序分析以及基底、腔面和上皮-间质转化（EMT）标志物表达显示出不同模式；某些细胞系主要表达基底或腔面标志物，而其他细胞系则表现出混合表达。SCaBER表达高水平的基底和EMT标志物以及低水平的腔面标志物，与真正的基底细胞一致。RT4V6是一个真正的腔面细胞系，仅显示高水平的腔面标志物。UC13、T24和UC3仅显示EMT标志物表达增加。RT112、UC6、UC9和UC14表达基底、腔面和EMT标志物。免疫组织化学分析验证了我们的发现。Ki67以阳性染色细胞的连续百分比进行评估。对异种移植瘤的形态学评估包括苏木精-伊红（H&E）染色和α-平滑肌肌动蛋白（α-SMA）染色。这些发现将有助于合理使用合适的模型来开发靶向疗法，以克服或操控BLCA中的治疗耐药机制。
