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Abstract：
Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.
摘要：
从腺癌到小细胞神经内分泌状态的跨分化与多种癌症类型的治疗抗性相关。为了深入了解转分化的潜在分子事件，我们对泛小细胞神经内分泌癌模型（称为PARCB）进行了多组学时程分析，使用人类前列腺基底细胞进行正向遗传转化，并确定共同的发育，弧形，和所有转换模型复制中的高熵轨迹。使用单细胞分辨率的进一步映射揭示了由ASCL1或ASCL2的互斥表达定义的两个不同的谱系。跨发育阶段的转录因子组的时间调节表明，细胞重编程先于神经元程序的诱导。TFAP4和ASCL1/2反馈被认为是ASCL1和ASCL2表达的潜在调节因子。我们的研究提供了时间转录模式，并揭示了前列腺癌和肺癌之间的泛组织相似性，以及与正常神经内分泌细胞状态的联系。
