MELANOMA, RESISTANCE, TARGETED THERAPY
In many cancers, an astonishing inter-and intra-tumor heterogeneity makes it challenging to define prognostic signatures and potential therapies. Moreover, there is increasing evidence that tumor cell heterogeneity dynamically changes during disease progression and therapy, with distinct subpopulations of tumor cells being controlled by specific gene regulatory networks. We have recently functionally characterized specific cell states that are activated at different steps of melanoma progression and that are potentially involved in the formation of resistance to targeted therapies. Based on this, we propose to characterize and functionally dissect distinct states observed during acquisition of resistance to targeted therapy in human melanoma. Specifically, we plan (1) to interfere with pathways downstream of CD271 during disease progression in vivo and resistance formation (2) to monitor emergence of a proliferative/invasive AXLhigh/MITFhigh state during treatment and to functionally assess pathways determining this state during disease progression and resistance formation and (3) to capture in an unbiased manner further states associated with drug tolerance and resistance formation in melanoma patients on treatment, by means of single cell analysis of fine needle biopsies. A better understanding of the cellular states functionally implicated in drug response and resistance formation might inform about alternative treatment strategies.