Research projects

Our main goal is to find new targets to prevent the development of metastasis and resistance to immunotherapy in melanoma. NGFR has emerged as a new candidate for the treatment of melanoma, associated with the de-differentiated phenotype responsible for tumour aggressiveness and resistance to targeted therapies. Throughout this project we have discovered that melanoma tumours secrete NGFR in small extracellular vesicles (SEVs) that are taken up by lymphatic endothelial cells, causing lymphangiogenesis and adhesion of tumour cells in lymph nodes. This facilitates the subsequent development of metastasis. Based on these results, we decided to explore the use of anti-NGFR agents to block melanoma metastasis. Indeed, both genetic and pharmacological NGFR inhibition reversed the lymphangiogenic phenotype, decreased local and distal metastasis and prolonged survival in preclinical models. Interestingly, the combination of a small molecule inhibitor of NGFR with immunotherapies such as anti-PD-L1 blocked both tumour growth and metastasis and, more importantly, also prevented the development of therapy resistance. In this regard, we have seen that NGFR is overexpressed in metastatic melanoma cells and in tumours resistant to immunotherapy. In melanoma patients, NGFR expression was increased in human lymph node and distal metastases relative to that in matched primary tumours. In addition, patients with high NGFR expression in their primary tumors are significantly associated with a worse response to immunotherapy and poor survival. Mechanistically, we postulate that NGFR expression is increased at the invasive front of tumours, which stimulates cell invasion and modifies immune recognition. Our data suggest that combining immunotherapy with NGFR inhibition could improve melanoma treatment by reducing the invasiveness of tumours and making them more sensitive to immunotherapy. We are currently investigating the mechanisms involved and the relevance of our findings in the clinical setting.