Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway
Abstract
Extracellular matrix (ECM) stiffening is a biophysical hallmark of solid tumors. Cutaneous melanoma is an aggressive malignancy characterized by high heterogeneity and phenotypic plasticity in which melanoma cells switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and therapy-resistant state. However, the impact of ECM stiffness on the diverse cellular phenotypes of melanoma remains poorly defined. Here, we show that melanoma cell subpopulations differ in their responses to mechanical signals. Compared to melanocytic/transitory cells, dedifferentiated cells exhibited heightened sensitivity to stiff collagen matrices, characterized by increased cell spreading, focal adhesion maturation, YAP nuclear translocation and contractility. ECM stiffening enhanced proliferation, migration and invasion in dedifferentiated cells, whereas highly proliferative and poorly migratory melanocytic/transitory cells were less affected by collagen stiffness. Importantly, a soft ECM sensitized dedifferentiated cells, but not melanocytic/transitory cells, to BRAF/MEK inhibition. Mechanistically, the mechanosensitivity of dedifferentiated cells relies on collagen receptors DDR1 and DDR2, which control cytoskeleton reorganization and YAP mechanosignaling. Genetic or pharmacological inhibition of DDR, actomyosin contractility, or YAP suppressed stiffness-induced proliferation and migration, reduced traction forces, and restored sensitivity to targeted therapy in dedifferentiated cells. Conversely, ectopic DDR1/DDR2 expression confers mechanosensitive properties to melanocytic cells. Our results thus reveal that phenotypic plasticity endows dedifferentiated melanoma cells with increased addiction to mechanical cues and implicate DDR1/2-YAP-dependent signaling in this aggressive behavior.
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BibTeX
@article{lecacheur2026extracellular,
title = {{Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway}},
author = {Margaux Lecacheur and Ilona Berestjuk and Alexandrine Carminati and Mira Rabbaa and Océane Bouvet and Serena Diazzi and Pierric Biber and Christopher Rovera and Marie Irondelle and Frédéric Larbret and Virginie Prod’homme and Christophe Girard and Marcel Deckert and Sophie Tartare-Deckert},
journal = {Oncogenesis},
year = {2026},
month = jun,
doi = {10.1038/s41389-026-00636-y},
url = {https://hal.science/hal-05762626v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Extracellular matrix stiffness determines the phenotypic behavior of dedifferentiated melanoma cells through a DDR1/2-dependent YAP mechanotransduction pathway
AU - Margaux Lecacheur
AU - Ilona Berestjuk
AU - Alexandrine Carminati
AU - Mira Rabbaa
AU - Océane Bouvet
AU - Serena Diazzi
AU - Pierric Biber
AU - Christopher Rovera
AU - Marie Irondelle
AU - Frédéric Larbret
AU - Virginie Prod’homme
AU - Christophe Girard
AU - Marcel Deckert
AU - Sophie Tartare-Deckert
PY - 2026
DA - 2026/06/13
JO - Oncogenesis
DO - 10.1038/s41389-026-00636-y
UR - https://hal.science/hal-05762626v1
AB - Extracellular matrix (ECM) stiffening is a biophysical hallmark of solid tumors. Cutaneous melanoma is an aggressive malignancy characterized by high heterogeneity and phenotypic plasticity in which melanoma cells switch from a proliferative and differentiated phenotype to an invasive, dedifferentiated and therapy-resistant state. However, the impact of ECM stiffness on the diverse cellular phenotypes of melanoma remains poorly defined. Here, we show that melanoma cell subpopulations differ in their responses to mechanical signals. Compared to melanocytic/transitory cells, dedifferentiated cells exhibited heightened sensitivity to stiff collagen matrices, characterized by increased cell spreading, focal adhesion maturation, YAP nuclear translocation and contractility. ECM stiffening enhanced proliferation, migration and invasion in dedifferentiated cells, whereas highly proliferative and poorly migratory melanocytic/transitory cells were less affected by collagen stiffness. Importantly, a soft ECM sensitized dedifferentiated cells, but not melanocytic/transitory cells, to BRAF/MEK inhibition. Mechanistically, the mechanosensitivity of dedifferentiated cells relies on collagen receptors DDR1 and DDR2, which control cytoskeleton reorganization and YAP mechanosignaling. Genetic or pharmacological inhibition of DDR, actomyosin contractility, or YAP suppressed stiffness-induced proliferation and migration, reduced traction forces, and restored sensitivity to targeted therapy in dedifferentiated cells. Conversely, ectopic DDR1/DDR2 expression confers mechanosensitive properties to melanocytic cells. Our results thus reveal that phenotypic plasticity endows dedifferentiated melanoma cells with increased addiction to mechanical cues and implicate DDR1/2-YAP-dependent signaling in this aggressive behavior.
SN - 2157-9024
SN - 2157-9024
ER -