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  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.

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

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 Zusammenfassung: 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.

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 Datum: 2023-03-20
 Publikationsstatus: Online veröffentlicht
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 Art der Begutachtung: -
 Identifikatoren: ISI: 000968443900001
DOI: 10.3390/cancers15061866
PMID: 36980752
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Titel: CANCERS
Genre der Quelle: Zeitschrift
 Urheber:
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 15 (6) Artikelnummer: 1866 Start- / Endseite: - Identifikator: -