MET receptor serves as a promising target in melanoma brain metastases

Torben Redmer; E. Schumann; Kristin Hilborn; Martin Weidemeier; Stephan Nowak; Henry Schroeder; Anna Vidal; Helena Radbruch; A. Lehman; Susanne Kreuzer-Redmer; Karsten Juerchott; Josefine Radke

doi:10.1007/s00401-024-02694-1

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Title (eng)

MET receptor serves as a promising target in melanoma brain metastases

Author

Torben Redmer

University of Veterinary Medicine Vienna

E. Schumann

Kristin Hilborn

Martin Weidemeier

Stephan Nowak

Henry Schroeder

Anna Vidal

University of Veterinary Medicine Vienna

Helena Radbruch

A. Lehman

Susanne Kreuzer-Redmer

University of Veterinary Medicine Vienna

Karsten Juerchott

Josefine Radke

Abstract (eng)

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.

Keywords (eng)

MelanomaBrain MetastasisTAMsITGB7Interferon SignalingMET Receptor

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4433

DOI

10.1007/s00401-024-02694-1

Is in series

Title (eng)