Non-Oncogene Addiction of IKRAS/I-Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ

• Published in: Cancers 2023-03, Vol.15 (6)
• Main Authors: Spella, Magda, Ntaliarda, Giannoula, Skiadas, Georgios, Lamort, Anne-Sophie, Vreka, Malamati, Marazioti, Antonia, Lilis, Ioannis, Bouloukou, Eleni, Giotopoulou, Georgia A, Pepe, Mario A. A, Weiss, Stefanie A. I, Petrera, Agnese, Hauck, Stefanie M, Koch, Ina, Lindner, Michael, Hatz, Rudolph A, Behr, Juergen, Arendt, Kristina A. M, Giopanou, Ioanna, Brunn, David, Savai, Rajkumar, Jenne, Dieter E, de Château, Maarten, Yull, Fiona E, Blackwell, Timothy S, Stathopoulos, Georgios T
• Format: Article
• Language: English
• Subjects: Cancer; Development and progression; Genetic aspects; Health aspects; Mutation (Biology)
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15061866

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. The aim of this study was to investigate the pathways through which KRAS-mutant cancers foster their growth, thereby unravelling novel therapeutic targets. We show that KRAS-mutant tumors secrete the protein versican, which then drives the activation of NF-κB kinase (IKK) β in a type of host immune cells called macrophages. Following this activation, macrophages fuel the tumor with interleukin (IL)-1β, to close an inflammatory loop through which KRAS-mutant cancers attract host immune cells to the tumor site to accelerate tumor growth and aggressiveness. Importantly, we show that targeting IL-1β and/or versican can be an effective treatment for KRAS-mutant cancers, holding great promise for cancer patients. 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.