Chromatin Remodeling Alterations and Consequences for Melanoma Metastasis

Melanoma is the most lethal skin cancer and when detected at an advanced stage in which cells have spread throughout the body (known as metastasis), success of currently available therapies is limited. The brain is a common site of metastasis for multiple cancer types and is associated with poor survival. Melanoma brain metastases (MBMs) occur in ~60% of metastatic melanoma patients and up to 90% at autopsy, illustrating melanoma’s striking ability to access and colonize the brain. Recent genomic sequencing studies revealed an enrichment of mutations in SWI/SNF chromatin remodeling subunits, particularly ARID2, in MBMs. However, it remains unclear how these mutations play a role in metastasis.

Chromatin regulators are emerging as promising candidates for cancer therapy because of their broad roles in orchestrating genome function, as well as their frequent alterations in cancer. We found that in ARID2-deficient melanoma tumors, cancer cells are more successfully able to metastasize to distal organs in animal models. We hypothesize that genetic loss of ARID2 may also confer an advantage for melanoma metastasis to survive in the brain environment. Here, we will carefully investigate the role of ARID2 in metastasis using brain-tropic human melanoma cells in animal models through a series of experiments that recapitulate various aspects of the metastatic process to the brain and other organs. We will investigate the genes and pathways that allow these cells to do so, which will provide insight into the poorly understood mechanisms of melanoma metastasis. Finally, our study will help improve our understanding of brain metastasis with potential impact for the treatment of melanoma patients.