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Open Access 01-06-2024 | Melanoma | Original Paper

MET receptor serves as a promising target in melanoma brain metastases

Authors: Torben Redmer, Elisa Schumann, Kristin Peters, Martin E. Weidemeier, Stephan Nowak, Henry W. S. Schroeder, Anna Vidal, Helena Radbruch, Annika Lehmann, Susanne Kreuzer-Redmer, Karsten Jürchott, Josefine Radke

Published in: Acta Neuropathologica | Issue 1/2024

Abstract

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 Iba1^high 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-MET^Y1234/1235 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.

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Title: MET receptor serves as a promising target in melanoma brain metastases
Authors: Torben Redmer
Elisa Schumann
Kristin Peters
Martin E. Weidemeier
Stephan Nowak
Henry W. S. Schroeder
Anna Vidal
Helena Radbruch
Annika Lehmann
Susanne Kreuzer-Redmer
Karsten Jürchott
Josefine Radke
Publication date: 01-06-2024
Publisher: Springer Berlin Heidelberg
Keywords: Melanoma
Melanoma
Metastasis
Interferon
Published in: Acta Neuropathologica / Issue 1/2024
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-024-02694-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

MET receptor serves as a promising target in melanoma brain metastases

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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