Clonal tracking in vivo in melanoma patient-derived xenografts
Most melanomas are diagnosed at an early stage, where surgical excision is curative in most cases, but a substantial fraction of patients is at high risk of developing metastatic disease. The management of metastatic patients is still challenging, even if they may benefit from neoadjuvant and adjuvant immunotherapy or targeted therapy.
The project aims to trace and characterize cell clones that expand within a tumor in human-in-mouse melanoma models already in place in the laboratory of the proponent. Primary melanomas, carrying BRAF or NRAS mutations, are transplanted in immune-deficient mice, and tumor cell composition analysed during in vivo melanoma development, acquisition of resistance after treatment with a combination of dabrafenib and trametinib or trametinib only, and during metastasis dissemination. Individual cells will be tracked in the animal by means of cellular barcoding to: i) monitor clone expansion during tumor growth, regression following treatment and metastasis formation; ii) investigate tumor cell composition through single cell RNA sequencing; iii) identify novel vulnerabilities by analysing melanoma cells transduced with shRNA actionable libraries in vivo.