Melanomas can have multiple coexisting cell states, including proliferative (PRO) versus invasive (INV) subpopulations that represent a "go or grow" trade-off; however, how these populations interact is poorly understood. Using a combination of zebrafish modeling and analysis of patient samples, we show that INV and PRO cells form spatially structured heterotypic clusters and cooperate in the seeding of metastasis, maintaining cell state heterogeneity. INV cells adhere tightly to each other and form clusters with a rim of PRO cells. Intravital imaging demonstrated cooperation in which INV cells facilitate dissemination of less metastatic PRO cells. We identified the TFAP2 neural crest transcription factor as a master regulator of clustering and PRO/INV states. Isolation of clusters from patients with metastatic melanoma revealed a subset with heterotypic PRO-INV clusters. Our data suggest a framework for the co-existence of these two divergent cell populations, in which heterotypic clusters promote metastasis via cell-cell cooperation.
2808 - 2825.e10
Weill Cornell/Rockefeller Memorial Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA; Computational and Systems Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Neural Crest, Animals, Zebrafish, Melanoma, Neoplasm Metastasis, Cluster Analysis, Gene Expression Regulation, Neoplastic, Neoplastic Cells, Circulating