Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.
- Spella, M.
- Ntaliarda, G.
- Skiadas, G.
- Lamort, A. S.
- Vreka, M.
- Marazioti, A.
- Lilis, I.
- Bouloukou, E.
- Giotopoulou, G. A.
- Pepe, M. A. A.
- Weiss, S. A. I.
- Petrera, A.
- Hauck, S. M.
- Koch, I.
- Lindner, M.
- Hatz, R. A.
- Behr, J.
- Arendt, K. A. M.
- Giopanou, I.
- Brunn, D.
- Savai, R.
- Jenne, D. E.
- de Château, M.
- Yull, F. E.
- Blackwell, T. S.
- Stathopoulos, G. T.
Keywords
- bioluminescence
- cancer
- inflammation
- interleukin-1β
- non-oncogene addiction
- nuclear factor-κB
