Associated Project 2

1. Applicant

2. Topic

Plasticity of melanoma invasion and interaction with the tumor stroma


3. Short summary

Cell invasion and metastasis are the key steps of melanoma progression and fatal outcome. Recent evidence from other tumors suggests that the cellular and molecular mechanisms leading to cancer invasion and metastasis in vivo are diverse and that significant molecular plasticity affects the efficiency of therapeutic interference. In this project we aim at dissecting mechanisms of melanoma invasion using 3D in vitro culture and in vivo microscopy to address molecular plasticity prompting secondary outgrowth despite experimental interference. Based on our previous research focus, key regimens are inhibition of promigratory adhesion receptors ß1 integrins, tissue-degrading surface MT1-MMP/MMP-14, x-ray, gamma irradiation and chemotherapy by darcarbazine, either alone or in combination. In vitro response to molecular interference will be monitored as invasion and survival in 3D extracellular matrix-based assays in the absence or presence of stromal cells. The underlying signaling and transcriptional control pathways of plasticity (e.g. YB-1, c-Jun, others) will be assayed in collaboration with network partners. In vivo response to interference of invasion, interaction with the tumor microenvironment, and metastasis will be studied by intravital multiphoton microscopy of orthotopically grafted fluorescent melanoma lesions as well as experimental metastasis. These studies will provide cellular and molecular mechanisms of melanoma invasion and reveal thus far neglected adaptation and resistance to therapy.

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