1. Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ
- Author
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Magda Spella, Giannoula Ntaliarda, Georgios Skiadas, Anne-Sophie Lamort, Malamati Vreka, Antonia Marazioti, Ioannis Lilis, Eleni Bouloukou, Georgia A. Giotopoulou, Mario A. A. Pepe, Stefanie A. I. Weiss, Agnese Petrera, Stefanie M. Hauck, Ina Koch, Michael Lindner, Rudolph A. Hatz, Juergen Behr, Kristina A. M. Arendt, Ioanna Giopanou, David Brunn, Rajkumar Savai, Dieter E. Jenne, Maarten de Château, Fiona E. Yull, Timothy S. Blackwell, and Georgios T. Stathopoulos
- Subjects
nuclear factor-κB ,interleukin-1β ,cancer ,inflammation ,non-oncogene addiction ,bioluminescence ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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.
- Published
- 2023
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