谱系可塑性是影响治疗结果的癌症进展的标志，但介导这一过程的机制仍不清楚。在这里，我们介绍了一个多功能的体内平台来研究前列腺癌进展过程中的神经内分泌谱系转化。具有人类相关驱动突变（Rb1-/-；Trp53-/-；cMyc 或 Pten-/-；Trp53-/-；cMyc）的移植小鼠前列腺类器官会发展为腺癌，但只有那些 Rb1 缺失的细胞才会进展为侵袭性 ASCL1 神经内分泌腺癌前列腺癌（NEPC）对雄激素受体信号抑制剂具有耐药性。值得注意的是，这种转变需要传统类器官培养无法复制的体内微环境。利用多重免疫荧光和空间转录组学，我们揭示了 ASCL1 细胞起源于 KRT8 管腔细胞，并进展为转录异质性 ASCL1；KRT8-NEPC。已建立的 NEPC 中 Ascl1 缺失会导致短暂消退，随后复发，但移植前将其删除会消除谱系可塑性，导致去势敏感腺癌。该动态模型强调了治疗时机的重要性，并提供了一个识别其他谱系可塑性驱动因素的平台。© 2024。作者。

Lineage plasticity is a hallmark of cancer progression that impacts therapy outcomes, yet the mechanisms mediating this process remain unclear. Here, we introduce a versatile in vivo platform to interrogate neuroendocrine lineage transformation throughout prostate cancer progression. Transplanted mouse prostate organoids with human-relevant driver mutations (Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1+ neuroendocrine prostate cancer (NEPC) resistant to androgen receptor signaling inhibitors. Notably, this transition requires an in vivo microenvironment not replicated by conventional organoid culture. Using multiplexed immunofluorescence and spatial transcriptomics, we reveal that ASCL1+ cells arise from KRT8+ luminal cells, progressing into transcriptionally heterogeneous ASCL1+;KRT8- NEPC. Ascl1 loss in established NEPC causes transient regression followed by recurrence, but its deletion before transplantation abrogates lineage plasticity, resulting in castration-sensitive adenocarcinomas. This dynamic model highlights the importance of therapy timing and offers a platform to identify additional lineage plasticity drivers.© 2024. The Author(s).