de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Department of Pathology, Cliniques Universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
Hepatology. 2021 Sep;74(3):1445-1460. doi: 10.1002/hep.31834.
Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis.
To this end, we generated a mouse model which combines cholangiocyte-specific expression of Kras with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis. Histological and transcriptomic analyses of the mouse precursor lesions and iCCA were performed and compared with human analyses. The function of genes overexpressed during tumorigenesis was investigated in human cell lines. We found that mice expressing Kras in cholangiocytes and fed a DDC diet developed cholangitis, ductular proliferations, intraductal papillary neoplasms of bile ducts (IPNBs), and, eventually, iCCAs. The histology of mouse and human IPNBs was similar, and mouse iCCAs displayed histological characteristics of human mucin-producing, large-duct-type iCCA. Signaling pathways activated in human iCCA were also activated in mice. The identification of transition zones between IPNB and iCCA on tissue sections, combined with RNA-sequencing analyses of the lesions supported that iCCAs derive from IPNBs. We further provide evidence that tensin-4 (TNS4), which is stimulated by KRAS and SRY-related HMG box transcription factor 17, promotes tumor progression.
We developed a mouse model that faithfully recapitulates human iCCA tumorigenesis and identified a gene cascade which involves TNS4 and promotes tumor progression.
早期诊断和治疗肝内胆管癌（iCCA）对于改善治疗效果至关重要，但目前对于 iCCA 前体病变的发生和发展的信息有限。因此，需要使用能够真实再现人类肿瘤发生过程的实验模型，来鉴定驱动癌前病变形成及其向侵袭性肿瘤进展的机制。
为此，我们构建了一种小鼠模型，该模型结合了胆管细胞特异性表达 Kras 与 3,5-二乙氧基羰基-1,4-二氢吡啶（DDC）饮食诱导的炎症，以模拟胆管炎患者的 iCCA 发生。对小鼠前体病变和 iCCA 进行了组织学和转录组学分析，并与人类分析进行了比较。在人类细胞系中研究了肿瘤发生过程中过表达基因的功能。我们发现，在胆管细胞中表达 Kras 并给予 DDC 饮食的小鼠发生胆管炎、胆管增生、胆管内乳头状肿瘤（IPNBs），最终发展为 iCCA。小鼠和人类 IPNBs 的组织学相似，并且小鼠 iCCA 显示出人类黏蛋白产生的大胆管型 iCCA 的组织学特征。在人类 iCCA 中激活的信号通路也在小鼠中被激活。组织切片中 IPNB 和 iCCA 之间过渡区的鉴定，以及对病变的 RNA 测序分析，支持 iCCA 来源于 IPNBs。我们进一步提供了证据表明，Tensin-4（TNS4）在 KRAS 和 SRY 相关 HMG 盒转录因子 17 的刺激下，促进肿瘤进展。
我们开发了一种能够真实再现人类 iCCA 肿瘤发生的小鼠模型，并确定了一个涉及 TNS4 并促进肿瘤进展的基因级联。
