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Updated: Aug 10, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
The mechanical phenotypic plasticity of melanoma cell: an emerging driver of therapy cross-resistance
Serena Diazzi1,2, Sophie Tartare-Deckert3,4, Marcel Deckert5,6
1Université Côte d'Azur, INSERM, C3M, Microenvironment, Signaling and Cancer, 06200, Nice, France.
Abstract:
Advanced cutaneous melanoma is the deadliest form of skin cancer and one of the most aggressive human cancers. Targeted therapies (TT) against BRAF mutated melanoma and immune checkpoints blockade therapies (ICB) have been a breakthrough in the treatment of metastatic melanoma. However, therapy-driven resistance remains a major hurdle in the clinical management of the metastatic disease. Besides shaping the tumor microenvironment, current treatments impact transition states to promote melanoma cell phenotypic plasticity and intratumor heterogeneity, which compromise treatment efficacy and clinical outcomes. In this context, mesenchymal-like dedifferentiated melanoma cells exhibit a remarkable ability to autonomously assemble their own extracellular matrix (ECM) and to biomechanically adapt in response to therapeutic insults, thereby fueling tumor relapse. Here, we review recent studies that highlight mechanical phenotypic plasticity of melanoma cells as a hallmark of adaptive and non-genetic resistance to treatment and emerging driver in cross-resistance to TT and ICB. We also discuss how targeting BRAF-mutant dedifferentiated cells and ECM-based mechanotransduction pathways may overcome melanoma cross-resistance.
Insights
Melanoma cells develop resistance to targeted therapies (TT) and immune checkpoint blockade (ICB) through mechanical changes. Targeting these dedifferentiated cells and their extracellular matrix (ECM) may overcome treatment resistance.
Area of Science:
- Oncology
- Cancer Biology
- Dermatology
Background:
- Advanced cutaneous melanoma is an aggressive cancer with limited treatment options.
- Targeted therapies (TT) and immune checkpoint blockade (ICB) have improved outcomes but face resistance.
- Therapy-induced phenotypic plasticity and intratumor heterogeneity contribute to treatment failure.
Purpose of the Study:
- To review the role of mechanical phenotypic plasticity in melanoma resistance to TT and ICB.
- To explore the contribution of dedifferentiated melanoma cells and their extracellular matrix (ECM) to therapeutic resistance.
- To discuss potential strategies for overcoming cross-resistance.
Main Methods:
- Literature review of recent studies on melanoma cell plasticity, ECM, and mechanotransduction.
- Analysis of adaptive and non-genetic resistance mechanisms.
- Discussion of therapeutic targeting strategies.
Main Results:
- Melanoma cells exhibit mechanical phenotypic plasticity, enabling adaptation to therapeutic insults.
- Dedifferentiated melanoma cells assemble ECM and adapt biomechanically, promoting tumor relapse.
- This plasticity is a hallmark of adaptive resistance and a driver of cross-resistance to TT and ICB.
Conclusions:
- Mechanical phenotypic plasticity is a critical factor in melanoma's non-genetic resistance to current treatments.
- Targeting BRAF-mutant dedifferentiated cells and ECM-mediated mechanotransduction pathways shows promise for overcoming cross-resistance.
- Further research into targeting these mechanisms could improve clinical outcomes for metastatic melanoma.
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