Extracellular Vesicles as mediators of Pre-Metastatic Niche Formation in Melanoma

Every 2 minutes someone in the world is diagnosed with melanoma, so by the time you read this application dozens of new melanoma cases will be detected.

Beyond its growing incidence, cutaneous melanoma is the most aggressive type of skin cancer and notorious for its high metastatic propensity, which constitutes the primary cause of death for these patients. Cellular heterogeneity and plasticity are key features of melanoma, supporting disease progression.

The host laboratory has recently charted a functional map of the melanoma ecosystem and identified a cell population that fuels tumor growth (pre-EMT) and another that functions as metastasis-initiating cells (MICs).

Increasing evidence indicates that metastatic dissemination of MICs relies on the formation of favourable microenvironments, or pre-metastatic niches (PMN), at secondary sites, and that extracellular vesicles (EVs) shed by the primary tumour are key mediators of PMN formation.

I hypothesize that EVs produced by phenotypically distinct melanoma cells are likely to contain different biological information, and thus may exert different (possibly diverging) roles in PMNs formation.

In METMAP, I will (i) determine the melanoma cell state(s) contributing to the formation of PMNs via EVs; (ii) dissect the molecular mechanisms underlying PMN formation; and (iii) unravel how these mechanisms facilitate metastatic spreading.

I will leverage my background in EVs biology and establish melanoma cell state-reporters to track EV-mediated communication between melanoma subpopulations and PMNs.

Proximity labelling will be used to dissect the bioactive contents of EVs transferred to PMNs and perturbation experiments will be conducted to decipher this complex interplay.

Through METMAP, I will deliver a functional understanding of how distinct melanoma states contribute to the development of PMN and, ultimately, identify new targets for disruptive therapies that hinder melanoma metastasis.