ABSTRACT Melanomas metastasizing to different organs often display heterogenous responses to therapies such as BRAF inhibitor or anti-PD-1 (aPD-1) immunotherapy. This heterogeneity of responses may be due to strictly tumor cell-intrinsic biological differences or more likely co-adaptation of the tumors with organ site-specific microenvironments. However, most patient-centric studies of metastatic melanoma biology and/or therapeutic responses are limited to one tumor per patient, with a predominance of tumors from more accessible sites such as the skin. Thus, there is a dearth of clinically relevant knowledge of organ site-specific adaptations of melanoma metastases and their possible influence on therapeutic responses. This project will derive this knowledge through comprehensive analysis on not only melanoma lesions at distinct organ sites but also their adjacent and non-adjacent normal organ tissues from warm autopsies. Through integrative genomic and transcriptomic analysis of triplets of tumor, adjacent normal and non-adjacent normal specimens, this study sets out to dissect the co-evolution of the tumor and its host organs. The preliminary analyses have already revealed several pathway activations that may be related to MAPK inhibitor (MAPKi) or immune checkpoint blockade (ICB) resistance in the brain, liver and spleen metastases. Aiming for a larger set of specimens, the researchers will assess the tumor heterogeneity (at the genomic, transcriptomic and pathway activation levels), their association with metastatic growth and MAPKi/ICB response patterns in each metastatic organ. In parallel, the research team will examine the tumor-adjacent normal tissues' cellular composition and pathway activations. These will also be correlated with organ-specific tumor growth and treatment resistance. The PI's experiences in large omic integration analyses of MAPKi and ICB resistant tumors will be a tremendous asset for the success of the proposed work. This study is expected to discover and validate heretofore unknown determinants of organ-specific metastasis in melanoma and novel mechanism(s) of resistance to MAPKi and ICB.