Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Cancer. 2024 Nov;5(11):1641-1659. doi: 10.1038/s43018-024-00838-6. Epub 2024 Oct 11.
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.
谱系可塑性是癌症进展的标志，影响治疗效果，但介导这一过程的机制仍不清楚。在这里，我们引入了一种通用的体内平台，以研究整个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 缺失的才会进展为侵袭性、ASCL1 神经内分泌前列腺癌（NEPC），对雄激素受体信号抑制剂有抗性。值得注意的是，这种转变需要一个体内微环境，而常规类器官培养无法复制这种环境。通过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 腔细胞，并进展为转录异质性的 ASCL1；KRT8 NEPC。在已建立的 NEPC 中敲除 Ascl1 会导致短暂的消退，随后复发，但在移植前将其删除会阻止谱系可塑性，导致去势敏感的腺癌。这种动态模型强调了治疗时机的重要性，并提供了一个平台来识别其他谱系可塑性驱动因素。
