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

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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.