Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.

神经内分泌癌 (NEC) 是表达神经元分化标志物的肿瘤，可以在不同的解剖部位出现，但具有很强的组织学和临床相似性。在这里，我们报告了一系列人类 NEC 的染色质景观，并显示了对共同表观遗传程序激活的收敛性。我们特别关注治疗新发神经内分泌前列腺癌 (NEPC)，分析细胞系、患者来源的异种移植物 (PDX) 模型和人类临床样本，以显示基于神经元转录因子 ASCL1 表达的两种不同 NEPC 亚型的存在和 NEUROD1。而在细胞系和 PDX 模型中，这些亚型是相互排斥的，人类临床样本的单细胞分析显示出更复杂的肿瘤结构，其中亚型作为不同的亚群在同一肿瘤内共存。这些肿瘤亚群在遗传和表观遗传上不同，导致人类转移瘤的肿瘤内和肿瘤间异质性。总体而言，我们的结果提供了对 NEC 所显示的共同临床病理学特征的更深入理解。此外，人类 NEPC 的肿瘤内异质性表明需要同时靶向共存的肿瘤群体作为治疗策略。