Decoding the role of mitochondrial dynamics in the mesenchymal-to-amoeboid transition and melanoma metastasis

Objective

Tumor cell migration and invasion represent the foundation of cancer metastasis. It is therefore critical to better understand the mechanisms driving a specific subset of tumor cells to invade nearby tissues. Invasive cells are known to have an undifferentiated, mesenchymal-like state. However, under specific microenvironment conditions, mesenchymal cells become amoeboid, through a process known as the mesenchymal-to-amoeboid transition (MAT). Paradoxically, it is not the mesenchymal cells that are more metastatic-prone, but the amoeboid cells. What is not yet fully understood is the precise cellular mechanisms driving MAT. Emerging evidence show that mitochondria are closely linked with cellular motility, especially in cancer. Mitochondrial dynamics, consisting mainly in mitochondrial fusion, fission, intracellular trafficking and turnover, was proven to be involved in the migration of mesenchymal-like tumor cells. However, very little is known about the characteristics of lamellipodia-localized mitochondria in these cancer cells on one hand, and how it might influence MAT and the amoeboid phenotype on the other. Therefore, I first aim to evaluate the role of mitochondrial dynamics in tumor microenvironment-triggered MAT during the 3D invasion of melanoma cells by combining microfluidic and optogenetic approaches. Secondly, I will characterize the lamellipodia-localized mitochondria in terms of proteome, age, energetic and oxidative status, in mesenchymal-like melanoma cells using biochemical, microfluidic and proteomic approaches. By the end of the project, MitoMat would significantly improve the mechanistic understanding of how mitochondria are hijacked to fuel cancer cell motility, specifically within melanoma cells with different MAT phenotypes. If mitochondrial dynamics would prove to be a driver for both cell invasion modalities (mesenchymal and amoeboid), our results could represent the premises for a future migrastatic therapy, targeting cancer metastasis.