Functional analysis of canonical NF-kB signaling in colorectal cancer-associated fibroblasts
Final Report Abstract
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 an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we were now able to demonstrate a surprising tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulated intestinal epithelial cell proliferation, suppressed tumor cell apoptosis, enhanced accumulation of CD4(+)Foxp3(+) regulatory T cells, and induced angiogenesis, ultimately culminating a strong tumor promoting phenotype. Mechanistically we could show that in Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, was impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevented HGF secretion, and pharmacological inhibition of Met during the CAC model confirmed that enhanced tumor promotion is dependent on HGF-Met signaling in mucosa of Ikkβmutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients. However, a detailed analysis of IKKβ/NF-κB in CAFs in a model of invasive CRC that does not develop in the context of overt chronic inflammation remains to be performed.
Publications
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IKKß acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. J Exp Med. 2015 Dec 14;212(13):2253-66
Pallangyo CK, Ziegler PK, Greten FR
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Mesenchymal Cells in Colon Cancer. Gastroenterology. 2017 Apr;152(5):964-979
Koliaraki V, Pallangyo CK, Greten FR, Kollias G
