Cancers (Mar 2023)
Non-Oncogene Addiction of <i>KRAS</i>-Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ
- 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,
- Georgios T. Stathopoulos
Affiliations
- Magda Spella
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Giannoula Ntaliarda
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Georgios Skiadas
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Anne-Sophie Lamort
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Malamati Vreka
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Antonia Marazioti
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Ioannis Lilis
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Eleni Bouloukou
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Georgia A. Giotopoulou
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Mario A. A. Pepe
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Stefanie A. I. Weiss
- Comprehensive Pneumology Center and Institute for Lung Biology and Disease, Helmholtz Center Munich-German Research Center for Environmental Health, 81377 Munich, Germany
- Agnese Petrera
- Research Unit Protein Science-Core Facility Proteomics, Helmholtz Center Munich–German Research Center for Environmental Health, 80939 Munich, Germany
- Stefanie M. Hauck
- Research Unit Protein Science-Core Facility Proteomics, Helmholtz Center Munich–German Research Center for Environmental Health, 80939 Munich, Germany
- Ina Koch
- Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich and Asklepios Medical Center, 82131 Gauting, Germany
- Michael Lindner
- Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich and Asklepios Medical Center, 82131 Gauting, Germany
- Rudolph A. Hatz
- Center for Thoracic Surgery Munich, Ludwig-Maximilians-University of Munich and Asklepios Medical Center, 82131 Gauting, Germany
- Juergen Behr
- Department of Internal Medicine V, Ludwig-Maximilian-University of Munich, 81377 Munich, Germany
- Kristina A. M. Arendt
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Ioanna Giopanou
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- David Brunn
- Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Rajkumar Savai
- Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
- Dieter E. Jenne
- Comprehensive Pneumology Center and Institute for Lung Biology and Disease, Helmholtz Center Munich-German Research Center for Environmental Health, 81377 Munich, Germany
- Maarten de Château
- Buzzard Pharmaceutical, 17165 Stockholm, Sweden
- Fiona E. Yull
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA
- Timothy S. Blackwell
- Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN 37240, USA
- Georgios T. Stathopoulos
- Department of Physiology, Faculty of Medicine, University of Patras, 26504 Rio, Greece
- DOI
- https://doi.org/10.3390/cancers15061866
- Journal volume & issue
-
Vol. 15,
no. 6
p. 1866
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.
Keywords
