Dr Christophe GIRARD

Research Team

Microenvironment, Signaling and Cancer

Mechanobiology of cutaneous melanoma: role of mechanotransduction in plasticity, progression and therapeutic resistance

Abstract:

Melanoma tumors are highly heterogeneous and display remarkable cell plasticity, impacting both their progression and response to therapy. Therapies targeting the MAP Kinase pathway and immune checkpoint inhibitors have greatly improved the clinical outcome of metastatic cutaneous melanoma over the past decade. Yet, their long-term efficacy is limited by the acquisition of resistance through mutational or non-mutational mechanisms. Melanoma cells can switch between distinct cell states in response to several factors released in tumor microenvironment, referred to as the proliferative differentiated melanocytic and invasive dedifferentiated mesenchymal cell state. Tumor microenvironment is composed of various non-malignant cells and the extracellular matrix (ECM), whose physical nature greatly influences the progression and dissemination of various solid cancers as well as their therapy response.
Over the past 10 years, my research has mainly focused on the influence of the mechanical dialogue established between melanoma and its microenvironment on its plasticity, aggressiveness, and therapeutic resistance. Using different models of isogenic pairs of MAPKi-sensitive versus resistant melanoma cells and in vitro matrix models to analyze their response to changes in microenvironment mechanical properties, we found that melanoma cells that develop non-genetic resistance to MAPKi exhibit hypersensitivity to changes in extracellular matrix stiffness, mediated by contraction of the actin cytoskeleton and activation of the YAP and MRTF mechanosensors. These cells are also able to autonomously produce, assemble and remodel ECM that is protective against targeted therapies. Short-term exposure of parental MAPKi-sensitive melanoma cells to targeted therapies also induces mechanosignalling associated with deposition and remodelling of a fibrillar ECM in vitro and tumour rigidification in vivo. Interestingly, we show normalizing tumour stiffness enhances the efficacy of MAP kinase targeted therapies and delays tumour relapse. Finally, our results show that the acquisition of a dedifferentiated mesenchymal phenotype confers to melanoma cells an addiction to mechanical signals from the microenvironment, which promotes their aggressiveness and therapeutic resistance. We have shown that these effects depend on the activation of the collagen receptors DDR1 and DDR2 and the mechanosensor YAP via the reorganisation of the actomyosin cytoskeleton. Our work provides proof of principle that prevention of the MAPK-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients undergoing targeted therapies. Furthermore, it reveals a new role for DDR collagen receptors in melanoma mechanotransduction and progression and unveil a new vulnerability of dedifferentiated tumour cells, which could lead to the development of new therapeutic strategies targeting the dialogue between melanoma and its microenvironment.

Key words:

melanoma, extracellular matrix, mechanotransduction, cell plasticity, Discoidin domain receptor, YAP, MRTF, drug resistance