The overarching goal of our proposal is to develop a pre-cancer atlas of skin cancer. Skin is an ideal model to study the early phases of tumorigenesis because it is easily accessible for monitoring and non-invasive sampling. As the primary barrier against the environment, skin cells acquire large numbers of somatic mutations during each person’s life, fueling the growth of a diverse set of tumors from the various cell types in the organ. Our atlas will focus on the evolution of melanoma and cutaneous squamous cell carcinoma, which respectively arise from melanocytes and keratinocytes, because these are the deadliest forms of skin cancer, responsible for an estimated 20,000 deaths per year in the United States. Skin is also an immunologically active organ, providing opportunities to study the role of the immune system in cancer development. The role of immune surveillance in restraining skin cancers is illustrated by the dramatic increase of skin cancers in immunosuppressed individuals and the therapeutic successes of immune-based therapies. There is a major, unmet need to understand how the immune system interacts with tumors early in their development. To address this need, we designed an atlas to deduce how the immune system shapes tumor evolution during the transition from the pre-cancerous to cancerous stage. This will be accomplished through a series of molecular assays, performed on precursor-associated cancers (i.e., skin cancers with an adjacent pre-cursor lesion). Specifically, we will perform: 1. Bulk-cell DNA-sequencing, 2. T-cell and B-cell receptor clonotyping, 3. Bulk-cell RNA-sequencing, 4 spatial transcriptomics (10X Visium), 5. Spatial transcriptomics (10X Xenium), and 6. Spatial proteomics (IBEX) and compare the individual progression stages of each precursor-associated tumor. Collectively, these assays will reveal the key genetic and immunological events occurring at the transition from pre-cancer to cancer. Completion of these studies will reveal candidate diagnostic and prognostic biomarkers and possibly novel targets for therapeutic intervention. Our team has a collaborative track record of studying the evolution of skin cancers with clinical impact. Our work has contributed to the World Health Organization’s classification of melanoma, and we have discovered multiple biomarkers that have entered routine use in clinical practice to diagnose melanocytic neoplasms. As another major component of our center, we will establish a core, with dedicated personnel, charged with the goal of engaging with the HTAN network, the broader scientific community, and the lay public.

An estimated 20,000 deaths each year are attributable to skin cancer. There is a major need to better understand the molecular evolution of skin neoplasia, and to address this need, we propose development of a pre-cancer atlas of skin cancer. Completion of these studies will reveal diagnostic and prognostic markers of progression and open new avenues of therapeutic intervention.