Rethinking the biology of metastatic melanoma: a holistic approach

Hendrik H. L. D. Vandyck, Lisa M. Hillen*, Francesca M. Bosisio, Joost van den Oord, Axel Zur Hausen, Veronique Winnepenninckx*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

23 Citations (Web of Science)


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.

Original languageEnglish
Pages (from-to)603-624
Number of pages22
JournalCancer and Metastasis Reviews
Issue number2
Publication statusPublished - Jun 2021


  • Melanoma
  • Metastasis
  • Epithelial-mesenchymal transition
  • Phenotype switching
  • Dormancy
  • Warburg effect

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