Decoding molecular programs in melanoma brain metastases

Josefine Radke (), Elisa Schumann, Julia Onken, Randi Koll, Güliz Acker, Bohdan Bodnar, Carolin Senger, Sascha Tierling, Markus Möbs, Peter Vajkoczy, Anna Vidal, Sandra Högler, Petra Kodajova, Dana Westphal, Friedegund Meier, Frank Heppner, Susanne Kreuzer-Redmer, Florian Grebien, Karsten Jürchott and Torben Redmer ()
Additional contact information
Josefine Radke: University Medicine Greifswald
Elisa Schumann: German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte)
Julia Onken: German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte)
Randi Koll: German Cancer Consortium (DKTK), Partner Site Berlin, CCCC (Campus Mitte)
Güliz Acker: Berlin Institute of Health (BIH)
Bohdan Bodnar: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Carolin Senger: Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Sascha Tierling: Faculty NT, Saarland University
Markus Möbs: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Peter Vajkoczy: Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health
Anna Vidal: University of Veterinary Medicine Vienna
Sandra Högler: University of Veterinary Medicine Vienna
Petra Kodajova: University of Veterinary Medicine Vienna
Dana Westphal: University Hospital Carl Gustav Carus at TU Dresden
Friedegund Meier: University Hospital Carl Gustav Carus at TU Dresden
Frank Heppner: Berlin Institute of Health (BIH)
Susanne Kreuzer-Redmer: University of Veterinary Medicine Vienna
Florian Grebien: University of Veterinary Medicine Vienna
Karsten Jürchott: Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Center for Regenerative Therapies (BCRT)
Torben Redmer: University of Veterinary Medicine Vienna

Nature Communications, 2022, vol. 13, issue 1, 1-24

Abstract: Abstract Melanoma brain metastases (MBM) variably respond to therapeutic interventions; thus determining patient’s prognosis. However, the mechanisms that govern therapy response are poorly understood. Here, we use a multi-OMICS approach and targeted sequencing (TargetSeq) to unravel the programs that potentially control the development of progressive intracranial disease. Molecularly, the expression of E-cadherin (Ecad) or NGFR, the BRAF mutation state and level of immune cell infiltration subdivides tumors into proliferative/pigmented and invasive/stem-like/therapy-resistant irrespective of the intracranial location. The analysis of MAPK inhibitor-naive and refractory MBM reveals switching from Ecad-associated into NGFR-associated programs during progression. NGFR-associated programs control cell migration and proliferation via downstream transcription factors such as SOX4. Moreover, global methylome profiling uncovers 46 differentially methylated regions that discriminate BRAFmut and wildtype MBM. In summary, we propose that the expression of Ecad and NGFR sub- classifies MBM and suggest that the Ecad-to-NGFR phenotype switch is a rate-limiting process which potentially indicates drug-response and intracranial progression states in melanoma patients.

Date: 2022
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DOI: 10.1038/s41467-022-34899-x

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