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Updated: Aug 19, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Decoding molecular programs in melanoma brain metastases
Josefine Radke1,2,3,4, Elisa Schumann5,6, Julia Onken5,7
1Department of Pathology, University Medicine Greifswald, Greifswald, Germany. josefine.radke@med.uni-greifswald.de.
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.
Insights
Melanoma brain metastases (MBM) show distinct molecular subtypes. A switch from E-cadherin (Ecad) to NGFR expression indicates progression and potential therapy resistance in melanoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Melanoma brain metastases (MBM) exhibit variable responses to treatment, complicating prognosis.
- The underlying mechanisms driving therapeutic response and disease progression in MBM remain largely unknown.
Purpose of the Study:
- To investigate the molecular programs controlling progressive intracranial disease in MBM.
- To identify biomarkers predicting therapy response and prognosis in MBM.
Main Methods:
- Multi-omics approach integrating targeted sequencing (TargetSeq).
- Analysis of E-cadherin (Ecad) and NGFR expression, BRAF mutation status, and immune cell infiltration.
- Global methylome profiling.
Main Results:
- MBM tumors were classified into proliferative/pigmented and invasive/stem-like/therapy-resistant subtypes based on Ecad, NGFR, BRAF mutation, and immune infiltration.
- A switch from Ecad-associated to NGFR-associated programs was observed during progression in MAPK inhibitor-naive and refractory MBM.
- NGFR-associated programs influence cell migration and proliferation via SOX4.
- 46 differentially methylated regions distinguished BRAF-mutant from BRAF wildtype MBM.
Conclusions:
- E-cadherin (Ecad) and NGFR expression effectively subclassify MBM.
- The Ecad-to-NGFR phenotype switch is a critical process linked to drug response and intracranial progression in melanoma patients.
