Project Summary: This project will comprehensively catalogue the molecular alterations present in melanoma stroma in the setting of BRAF targeted therapy. Global transcriptomic, epigenomic and proteomic analyses will generate an unbiased profile in both human and mouse BRAF-mutant melanomas including paired baseline and post-treatment or relapse samples. These integrative and cross-species comparative analyses will define candidate driver stromal alterations that may dictate the response to BRAF targeted therapy. The functional relevance of candidate events will be validated through genetic or pharmacologic perturbation of the targets or their canonical pathways in vitro and in vivo. Further, confirmation of human relevance will be obtained through analysis of a large cohort of annotated human melanoma samples. Beyond discovery and validation, we will elucidate underlying mechanisms with the goal of converting these insights into rational therapeutic combinations designed to neutralize both tumor and stromal targets and avoid/minimize the emergence of BRAFi resistance.