Characterization of molecular mechanisms underlying phenotypic plasticity of metastasis-initiating cells (MICs) in melanoma..

Metastasis causes 90% of cancer-related deaths. Unfortunately, the identification of effective anti-metastatic therapeutic strategies has been hampered by our poor understanding of that the nature of metastasis-initiating cells (MIC) and mechanisms underlying their dissemination. MICs must be able to survive the various insults, including oxidative stress, these cells encounter during their journey to secondary sites. Critically, the host laboratory has identified a population of cells that is at the origin of metastases in melanoma, a disease with a very high metastatic propensity, and developed tools allowing the fate mapping and facile isolation of MICs and their progenies in vivo. I hereby propose to take advantage of these tools to monitor the dynamics of the transcriptomic landscape of MICs and their progenies, study their spatial distribution and interplay with their evolving surrounding tissue environments and investigate how different metabolic environments affect their biology. Given recent findings highlighting the crucial role of lysosomal machinery in the control of cell response to metabolic stress, and my particular interest in this pathway, I propose to test the hypothesis that the lysosomal pathway contributes to the survival of disseminated melanoma cells. Taking advantage of well-established in vitro and in vivo models, I will explore the therapeutic potential of targeting lysosomal metabolism as an effective anti-metastatic therapy in melanoma.

Keywords:Metastasis-initiating cells, phenotypic plasticity, lysosomal pathways

Disciplines:Regulation of metabolism, Cell death and senescence, Cell division, Cell growth and development, Intracellular compartments and transport