English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1 beta via Versican and Mononuclear IKK beta

Spella, M., Ntaliarda, G., Skiadas, G., Lamort, A.-S., Vreka, M., Marazioti, A., et al. (2023). Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1 beta via Versican and Mononuclear IKK beta. CANCERS, 15(6): 1866. doi:10.3390/cancers15061866.

Item is

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Spella, Magda, Author
Ntaliarda, Giannoula, Author
Skiadas, Georgios, Author
Lamort, Anne-Sophie, Author
Vreka, Malamati, Author
Marazioti, Antonia, Author
Lilis, Ioannis, Author
Bouloukou, Eleni, Author
Giotopoulou, Georgia A. A., Author
Pepe, Mario A. A., Author
Weiss, Stefanie A. I., Author
Petrera, Agnese, Author
Hauck, Stefanie M. M., Author
Koch, Ina, Author
Lindner, Michael, Author
Hatz, Rudolph A. A., Author
Behr, Juergen, Author
Arendt, Kristina A. M., Author
Giopanou, Ioanna, Author
Brunn, David1, Author           
Savai, Rajkumar1, Author           Jenne, Dieter E. E., Authorde Chateau, Maarten, AuthorYull, Fiona E. E., AuthorBlackwell, Timothy S. S., AuthorStathopoulos, Georgios T. T., Author more..
Affiliations:
1Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591698              

Content

show
hide
Free keywords: -
 Abstract: 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-kappa B kinase (IKK) beta in a type of host immune cells called macrophages. Following this activation, macrophages fuel the tumor with interleukin (IL)-1 beta, 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-1 beta 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)-1 beta and nuclear factor (NF)-kappa B inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1 beta via inflammatory versican signaling to macrophage inhibitor of NF-kappa B kinase (IKK) beta. Human pan-cancer and experimental NF-kappa B reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKK beta activation and IL-1 beta release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKK beta deletion prevents myeloid NF-kappa B activation and metastasis. Versican and IKK beta are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1 beta addiction is abolished by IL-1 beta and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKK beta in metastasis.

Details

show
hide
Language(s):
 Dates: 2023-03-20
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000968443900001
DOI: 10.3390/cancers15061866
PMID: 36980752
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: CANCERS
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 15 (6) Sequence Number: 1866 Start / End Page: - Identifier: -