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.
Institute for Computational Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA.
Dev Cell. 2021 Oct 25;56(20):2808-2825.e10. doi: 10.1016/j.devcel.2021.08.018. Epub 2021 Sep 15.
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.
黑色素瘤可能存在多种共存的细胞状态，包括增殖（PRO）和侵袭（INV）亚群，这代表了一种“前进或生长”的权衡；然而，这些群体如何相互作用还知之甚少。我们结合斑马鱼模型和对患者样本的分析表明，INV 和 PRO 细胞形成空间结构异质簇，并在转移的播种中合作，维持细胞状态异质性。INV 细胞彼此紧密附着，并形成带有 PRO 细胞边缘的簇。活体成像显示了合作，其中 INV 细胞促进了转移能力较低的 PRO 细胞的扩散。我们确定了 TFAP2 神经嵴转录因子是聚类和 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簇显示出具有异型 PRO-INV 簇的亚群。我们的数据为这两种不同细胞群体共存的框架提供了依据，其中异型簇通过细胞间合作促进转移。
