Although melanoma is notorious for its high degree of heterogeneity and plasticity^1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.

尽管黑色素瘤因其高度异质性和可塑性而臭名昭著^1,2，但细胞状态多样性的起源和程度仍然知之甚少。同样，尚不清楚重叠或不同的黑色素瘤亚群是否支持生长和转移扩散。在这里，通过结合小鼠遗传学、单细胞和空间转录组学、谱系追踪和定量建模，我们提供了肿瘤生长分层模型的证据，该模型反映了细胞命运规范和胚胎神经嵴分化背后的细胞和分子逻辑。 。我们表明，致瘤能力与空间局部的血管周围生态位有关，这是一种通过内皮细胞建立的细胞间通讯途径获得的表型。与只有一小部分细胞注定要促进生长的模型一致，对具有间充质样状态的黑色素瘤细胞群的时间单细胞追踪显示，这些细胞不会促进原发性肿瘤生长，而是构成一群转移起始细胞，在传播到次级器官时转换细胞身份。我们的数据提供了黑色素瘤细胞状态多样性和轨迹的空间和时间解析图，并表明支持生长和转移的能力仅限于不同的细胞池。这些表型能力可以在暴露于特定的生态位信号后动态获得，这一观察结果保证了开发干扰此类微环境线索的癌细胞重编程活性的治疗策略。