Functional analysis of canonical NF-kB signaling in colorectal cancer-associated fibroblasts

肿瘤相关成纤维细胞(CAF)是包括结直肠癌(CRC)在内的多种癌症微环境中的一种重要细胞类型。在过去的几年里，我们能够确定在髓系和上皮细胞中依赖IKKB/NF-kB的各种促肿瘤功能，这些功能影响结直肠肿瘤的启动、促进和进展。最近，在皮肤癌、乳腺癌和胰腺癌的肿瘤模型中，CAF被证明具有促炎症的NF-kB信号，并被认为具有促肿瘤功能。然而，在一个有效的结直肠癌遗传模型中，缺乏对核因子-kB信号的深入分析。使用成纤维细胞特异性缺失IKKB的小鼠，我们获得了一些意想不到的结果，表明在结肠炎相关癌变过程中，成纤维细胞中的IKKB/NF-kB具有抗肿瘤作用。在这里，我们的目标是确定导致这种表型的潜在分子机制，并在不同的炎症相关性结肠癌和散发性结肠癌体内模型中对这一信号通路进行全面分析。

Cancer-associated fibroblasts (CAFs) comprise an important cell type in the microenvironment of various cancers including colorectal cancer (CRC). In the last years we were able to define various IKKb/NF-kB dependent pro-tumorigenic functions in myeloid and epithelial cells that affected colorectal tumor initiation, promotion and progression. Recently, in tumor models of skin, mammary and pancreatic cancer CAFS were shown to have a pro-inflammatory NF-kB signature and suggested to provide pro-tumorigenic functions. However, an in depth analysis of NF-kB signaling in a valid genetic model of colorectal cancer is missing. Using a mouse with fibroblast-specific deletion of IKKb we obtained some unexpected results suggesting an anti-tumorigenic function of IKKb/NF-kB in fibroblasts during colitis-associated carcinogenesis. Here we aim to identify the underlying molecular mechanisms responsible for this phenotype and to provide a comprehensive analysis of this signaling pathway in different in vivo models of inflammation-associated and sporadic colon cancer.