phaidra.vetmeduni.ac.at o:4433 DOI 10.1007/s00401-024-02694-1 MET receptor serves as a promising target in melanoma brain metastases The development of brain metastases hallmarks disease progression in 20–40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival. eng Melanoma Brain Metastasis TAMs ITGB7 Interferon Signaling MET Receptor 2025-10-02T12:22:41.992Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Redmer;Torben; FN:Torben Redmer X-ORCID:https://orcid.org/0000-0002-0050-9478 END:VCARD BEGIN:VCARD VERSION:3.0 N:Schumann;E.; FN:E. Schumann END:VCARD BEGIN:VCARD VERSION:3.0 N:Hilborn;Kristin; FN:Kristin Hilborn END:VCARD BEGIN:VCARD VERSION:3.0 N:Weidemeier;Martin; FN:Martin Weidemeier END:VCARD BEGIN:VCARD VERSION:3.0 N:Nowak;Stephan; FN:Stephan Nowak END:VCARD BEGIN:VCARD VERSION:3.0 N:Schroeder;Henry; FN:Henry Schroeder END:VCARD BEGIN:VCARD VERSION:3.0 N:Vidal;Anna; FN:Anna Vidal END:VCARD BEGIN:VCARD VERSION:3.0 N:Radbruch;Helena; FN:Helena Radbruch END:VCARD BEGIN:VCARD VERSION:3.0 N:Lehman;A.; FN:A. Lehman END:VCARD BEGIN:VCARD VERSION:3.0 N:Kreuzer-Redmer;Susanne; FN:Susanne Kreuzer-Redmer X-ORCID:https://orcid.org/0000-0001-9425-3356 END:VCARD BEGIN:VCARD VERSION:3.0 N:Juerchott;Karsten; FN:Karsten Juerchott END:VCARD BEGIN:VCARD VERSION:3.0 N:Radke;Josefine; FN:Josefine Radke END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 7199572 https://phaidra.vetmeduni.ac.at/o:4433 https://phaidra.vetmeduni.ac.at/api/object/o:4433/thumbnail LOMv1.0 discipline