Non-Oncogene Addiction of KRAS -Mutant Cancers to IL-1β via Versican and Mononuclear IKKβ.
Magda SpellaGiannoula NtaliardaGeorgios SkiadasAnne-Sophie LamortMalamati VrekaAntonia MaraziotiIoannis LilisEleni BouloukouGeorgia A GiotopoulouMario A A PepeStefanie A I WeissAgnese PetreraStefanie M HauckIna KochMichael LindnerRudolph A HatzJuergen BehrKristina A M ArendtIoanna GiopanouDavid BrunnSoni Savai PullamsettiDieter E JenneMaarten de ChâteauFiona E YullTimothy S BlackwellGeorgios T StathopoulosPublished in: Cancers (2023)
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.
Keyphrases
- nuclear factor
- wild type
- toll like receptor
- endothelial cells
- signaling pathway
- oxidative stress
- lps induced
- adipose tissue
- pi k akt
- induced pluripotent stem cells
- small cell lung cancer
- inflammatory response
- squamous cell carcinoma
- gene expression
- pluripotent stem cells
- dendritic cells
- squamous cell
- rna seq
- crispr cas
- bone marrow
- high throughput
- machine learning
- lymph node metastasis
- acute myeloid leukemia
- high resolution mass spectrometry