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Tumor-secreted versican co-opts myeloid IKKβ during metastasis

Spella, M.; Lamort, A. S.; Vreka, M.; Marazioti, A.; Lilis, I.; Ntaliarda, G.; Skiadas, G.; Bouloukou, E.; Giotopoulou, G. A.; Pepe, M. A.; Weiss, S. A.; Petrera, A.; Hauck, S. M.; Koch, I.; Lindner, M.; Hatz, R. A.; Behr, J.; Arendt, K. A.; Giopanou, I.; Brunn, D.; Savai, R.; Jenne, D. E.; Yull, F. E.; Blackwell, T.; Stathopoulos, G. T.

2021-05-22 cancer biology
10.1101/2021.05.20.444963 bioRxiv
Show abstract

The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-{kappa}B reporter mice and macrophages to discover that metastatic tumors trigger NF-{kappa}B activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-{kappa}B in tumor-associated macrophages via inhibitor of NF-{kappa}B kinase (IKK) {beta}, resulting in release of interleukin (IL)-1{beta} into the tumor microenvironment. Versican silencing in cancer cells or conditional IKK{beta} deletion in macrophages prevents myeloid NF-{kappa}B activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKK{beta} during metastasis and may foster the development of new therapies and diagnostic tools.

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