English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT

Released

Journal Article

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

MPS-Authors
/persons/resource/persons239422

Brunn,  David
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

/persons/resource/persons224330

Savai,  Rajkumar
Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

External Resource
No external resources are shared
Fulltext (restricted access)
There are currently no full texts shared for your IP range.
Fulltext (public)
There are no public fulltexts stored in PuRe
Supplementary Material (public)
There is no public supplementary material available
Citation

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.


Cite as: https://hdl.handle.net/21.11116/0000-000D-1BAC-4
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.