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.

黑色素瘤可以有多种共存的细胞状态，包括增殖 (PRO) 与侵袭性 (INV) 亚群，代表“去或成长”的权衡；然而，人们对这些人群如何相互作用却知之甚少。结合斑马鱼建模和患者样本分析，我们表明 INV 和 PRO 细胞形成空间结构的异型簇，并在转移的播种中合作，维持细胞状态的异质性。INV 细胞彼此紧密粘附并形成带有 PRO 细胞边缘的簇。活体成像显示了合作，其中 INV 细胞促进了较少转移的 PRO 细胞的传播。我们将 TFAP2 神经嵴转录因子确定为聚类和 PRO/INV 状态的主要调节因子。从转移性黑色素瘤患者中分离出的集群揭示了一个具有异型 PRO-INV 集群的子集。我们的数据表明了这两种不同细胞群共存的框架，其中异型簇通过细胞-细胞合作促进转移。