Defining the development and function of heterogeneous melanoma cell states in time and space

Summary: Abstract Body: Tumor heterogeneity plays an important role in metastatic dissemination and therapy resistance. Still, the mechanisms controlling the development of phenotypically and functionally distinctive cancer cell states remain poorly understood. Here, we used a genetically engineered melanoma mouse model to define the emergence of distinctive melanoma cell states and their interactions with surrounding stromal cell types in real-time and transcriptional pseudo-time. Using single-cell and spatial transcriptomics combined with highly multiplexed imaging approaches, we uncover cell state-defining transcriptional networks and cell-cell communication networks in murine models and validate them in tissues of human melanoma patients. We define the occupancy of cell state-defining transcription factors on chromatin in patient-derived melanoma cultures and determine their functions in gene knock-out studies. We also perturb cell state-specific cell-cell communication networks with genetic and pharmacological approaches in mouse and patient-derived models. Collectively, our data provide novel mechanistic insight into the development of specific melanoma cell states and their roles in disease progression. Markus Schober¹, Paola Angulo-Salgado¹, Tatsuya Ogawa¹, Min Hsu¹, Robert Stagnitta¹, Katherine Ventre¹, Pietro Berico¹, Milad Ibrahim¹, Iman Osman¹, Amanda Lund¹, Ito Mayumi¹, Eva Hernando¹ 1. New York University Grossman School of Medicine, New York, NY, United States. Pigmentation, Melanoma, and Melanoma Immune Surveillance