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Updated: Nov 8, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Rethinking the biology of metastatic melanoma: a holistic approach
Hendrik Hld Vandyck1, Lisa M Hillen2, Francesca M Bosisio3
1Department of Pathology, GROW-School for Oncology & Developmental Biology, Maastricht University Medical Center, MUMC+, PO Box 5800, 6202, AZ, Maastricht, The Netherlands.
Abstract:
Over the past decades, melanoma-related mortality has remained nearly stable. The main reason is treatment failure of metastatic disease and the inherently linked knowledge gap regarding metastasis formation. In order to elicit invasion, melanoma cells manipulate the tumor microenvironment, gain motility, and adhere to the extracellular matrix and cancer-associated fibroblasts. Melanoma cells thereby express different cell adhesion molecules like laminins, integrins, N-cadherin, and others. Epithelial-mesenchymal transition (EMT) is physiological during embryologic development, but reactivated during malignancy. Despite not being truly epithelial, neural crest-derived malignancies like melanoma share similar biological programs that enable tumorigenesis, invasion, and metastasis. This complex phenomenon is termed phenotype switching and is intertwined with oncometabolism as well as dormancy escape. Additionally, it has been shown that primary melanoma shed exosomes that create a favorable premetastatic niche in the microenvironment of secondary organs and lymph nodes. Although the growing body of literature describes the aforementioned concepts separately, an integrative holistic approach is missing. Using melanoma as a tumor model, this review will shed light on these complex biological principles in an attempt to clarify the mechanistic metastatic pathways that dictate tumor and patient fate.
Insights
Melanoma metastasis remains poorly understood, hindering treatment. This review integrates concepts like phenotype switching and exosome signaling to clarify the complex pathways driving melanoma invasion and patient outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Biology
Background:
- Melanoma mortality is stable due to treatment failure in metastatic disease.
- Understanding melanoma metastasis is crucial for improving patient outcomes.
- Current literature addresses metastatic mechanisms separately, lacking a holistic view.
Purpose of the Study:
- To provide an integrative review of melanoma metastasis.
- To clarify the mechanistic pathways dictating tumor and patient fate.
- To use melanoma as a model for understanding complex metastatic principles.
Main Methods:
- Literature review integrating concepts of tumor microenvironment manipulation, cell adhesion, epithelial-mesenchymal transition (EMT), phenotype switching, oncometabolism, and exosome-mediated premetastatic niche formation.
- Analysis of biological programs shared between neural crest-derived malignancies and melanoma.
- Synthesis of disparate research findings into a cohesive framework.
Main Results:
- Melanoma cells invade by manipulating the tumor microenvironment, gaining motility, and adhering to extracellular matrix and fibroblasts.
- Phenotype switching, intertwined with oncometabolism and dormancy escape, enables tumorigenesis, invasion, and metastasis.
- Primary melanoma exosomes establish premetastatic niches in secondary organs and lymph nodes.
Conclusions:
- An integrative understanding of melanoma metastasis is essential for developing effective treatments.
- Key mechanisms include tumor microenvironment modulation, cell adhesion dynamics, phenotype switching, and exosome signaling.
- Clarifying these interconnected pathways will improve the prediction and management of melanoma patient fate.
