Defining drivers and metastatic risk of AP-1 heterogeneity in melanoma

Surgical removal of early melanomas has a high survival rate of 98%, but metastasis, the spread of cancer to other sites in the body, brings that survival rate down to 50%. Interestingly, 17% of “high-risk” early melanomas (1-4 mm thick) metastasize to nearby lymph nodes, but why some of these tumors spread while others do not remains unclear. Imagine an adult with a full-time job somehow reverting to a toddler in their terrible-twos. Melanoma is known for its ability to revert like this between “differentiation states” in a melanocyte’s normal development, changing from a differentiated, pigment-producing state to an undifferentiated, aggressive state that is more likely to spread. Understanding how melanoma cells transition between these states could help identify new ways to prevent metastasis or predict the best treatment strategies for individual patients. Previously, we discovered that a family of proteins called AP-1 transcription factors plays a key role in regulating these transitions, but we don’t know what drives these AP-1 changes in the first place. Based on AP-1’s historical function, we think that surrounding membranes, white blood cells, and blood vessels (the “tumor microenvironment” or TME) influence AP-1 levels and drive invasive changes within the tumor. In this project, we aim to uncover the mechanisms controlling these transitions by using advanced imaging techniques on diverse patient tissue samples. We will capture high resolution snapshots of the melanoma TME, mapping dozens of cell types in each patient sample. Accounting for patient factors like age and sex, we will identify how the TME influences melanoma cell states and whether specific two-dimensional patterns are associated with worse outcomes such as metastasis. Our goal is to develop a model that can predict patient outcomes based on the AP-1 levels and spatial organization of cells in the tumor, ultimately guiding more personalized treatment approaches for melanoma patients.