| First Author | Spella M | Year | 2023 |
| Journal | Cancers (Basel) | Volume | 15 |
| Issue | 6 | PubMed ID | 36980752 |
| Mgi Jnum | J:334951 | Mgi Id | MGI:7449531 |
| Doi | 10.3390/cancers15061866 | Citation | Spella M, et al. (2023) Non-Oncogene Addiction of KRAS-Mutant Cancers to IL-1beta via Versican and Mononuclear IKKbeta. Cancers (Basel) 15(6) |
| abstractText | Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1beta and nuclear factor (NF)-kappaB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1beta via inflammatory versican signaling to macrophage inhibitor of NF-kappaB kinase (IKK) beta. Human pan-cancer and experimental NF-kappaB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKbeta activation and IL-1beta release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKbeta deletion prevents myeloid NF-kappaB activation and metastasis. Versican and IKKbeta are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1beta addiction is abolished by IL-1beta and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKbeta in metastasis. |
