| Autor: |
Fiona E. Yull, G Skiadas, David Brunn, Michael Lindner, M Spella, Giannoula Ntaliarda, Rajkumar Savai, Weiss Sa, Mario A.A. Pepe, Rudolf Hatz, Georgios T. Stathopoulos, Ioanna Giopanou, Petrera A, Ina Koch, Bouloukou E, Timothy S. Blackwell, Antonia Marazioti, Malamati Vreka, Georgia A. Giotopoulou, Ioannis Lilis, Dieter E. Jenne, K. Arendt, Juergen Behr, Stefanie M. Hauck, Anne-Sophie Lamort |
| Rok vydání: |
2021 |
| Předmět: |
|
| DOI: |
10.1101/2021.05.20.444963 |
| Popis: |
The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-κB reporter mice and macrophages to discover that metastatic tumors trigger NF-κB activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-κB in tumor-associated macrophages via inhibitor of NF-κB kinase (IKK) β, resulting in release of interleukin (IL)-1β into the tumor microenvironment. Versican silencing in cancer cells or conditional IKKβ deletion in macrophages prevents myeloid NF-κB 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 IKKβ during metastasis and may foster the development of new therapies and diagnostic tools. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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