The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.
The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1.
复制标题
前列腺癌的神经内分泌转变是动态的并且依赖于 ASCL1。
DOI：
10.1101/2024.04.09.588557
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Choi,Jungmin
中科院分区：
文献类型：
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作者：
Romero,Rodrigo;Chu,Tinyi;González-Robles,TaniaJ;Smith,Perianne;Xie,Yubin;Kaur,Harmanpreet;Yoder,Sara;Zhao,Huiyong;Mao,Chenyi;Kang,Wenfei;Pulina,MariaV;Lawrence,KaylaE;Gopalan,Anuradha;Zaidi,Samir;Yoo,Kwangmin;Choi,Jungmin
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+orPten−/−;Trp53−/−;cMyc+) develop adenocarcinomas, but only those withRb1deletion 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.Ascl1loss 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.
