To study the progression of bladder cancer from non–muscle-invasive to muscle-invasive disease, we have developed a novel toolkit that uses complementary approaches to achieve gene recombination in specific cell populations in the bladder urothelium in vivo , thereby allowing us to generate a new series of genetically engineered mouse models (GEMM) of bladder cancer. One method is based on the delivery of adenoviruses that express Cre recombinase in selected cell types in the urothelium, and a second uses transgenic drivers in which activation of inducible Cre alleles can be limited to the bladder urothelium by intravesicular delivery of tamoxifen. Using both approaches, targeted deletion of the Pten and p53 tumor suppressor genes specifically in basal urothelial cells gave rise to muscle-invasive bladder tumors. Furthermore, preinvasive lesions arising in basal cells displayed upregulation of molecular pathways related to bladder tumorigenesis, including proinflammatory pathways. Cross-species analyses comparing a mouse gene signature of early bladder cancer with a human signature of bladder cancer progression identified a conserved 28-gene signature of early bladder cancer that is associated with poor prognosis for human bladder cancer and that outperforms comparable gene signatures. These findings demonstrate the relevance of these GEMMs for studying the biology of human bladder cancer and introduce a prognostic gene signature that may help to stratify patients at risk for progression to potentially lethal muscle-invasive disease. Significance: Analyses of bladder cancer progression in a new series of genetically engineered mouse models has identified a gene signature of poor prognosis in human bladder cancer.

中文翻译：

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膀胱癌的新型小鼠模型确定了与疾病进展风险相关的预后特征

为了研究膀胱癌从非肌肉侵袭性疾病到肌肉侵袭性疾病的进展，我们开发了一种新的工具包，该工具包使用补充方法在体内膀胱尿道上皮的特定细胞群中实现基因重组，从而使我们能够生成新系列膀胱癌基因工程小鼠模型（GEMM）。一种方法是基于在尿路上皮的选定细胞类型中表达Cre重组酶的腺病毒的递送，第二种方法使用转基因驱动程序，其中可通过膀胱内递送他莫昔芬将诱导型Cre等位基因的激活限制在膀胱尿路上皮。使用这两种方法，有针对性地删除基底尿路上皮细胞中的 Pten 和 p53 肿瘤抑制基因会导致肌肉侵袭性膀胱肿瘤。此外，基底细胞中出现的浸润前病变显示出与膀胱肿瘤发生相关的分子途径的上调，包括促炎途径。跨物种分析将早期膀胱癌的小鼠基因特征与人类膀胱癌进展特征进行比较，发现了早期膀胱癌的保守 28 个基因特征，该特征与人类膀胱癌的不良预后相关，并且优于类似的基因特征。这些发现证明了这些 GEMM 在研究人类膀胱癌生物学方面的相关性，并引入了一种预后基因特征，可能有助于对有进展为潜在致命性肌肉侵袭性疾病风险的患者进行分层。意义：对一系列新的基因工程小鼠模型中膀胱癌进展的分析发现了人类膀胱癌预后不良的基因特征。