Romero, Rodrigo, Chu, Tinyi, González Robles, Tania J, Smith, Perianne, Xie, Yubin, Kaur, Harmanpreet, Yoder, Sara, Zhao, Huiyong, Mao, Chenyi, Kang, Wenfei, Pulina, Maria V, Lawrence, Kayla E, Gopalan, Anuradha, Zaidi, Samir, Yoo, Kwangmin, Choi, Jungmin, Fan, Ning, Gerstner, Olivia, Karthaus, Wouter R, DeStanchina, Elisa, Ruggles, Kelly V, Westcott, Peter MK, Chaligné, Ronan, Pe'er, Dana, Sawyers, Charles L (October 2024) The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1. Nature Cancer. ISSN 2662-1347 (Public Dataset)
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Abstract
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > prostate cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program CSHL labs > Westcott lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 11 October 2024 |
| Date Deposited: | 15 Oct 2024 13:13 |
| Last Modified: | 15 Oct 2024 13:13 |
| Related URLs: | |
| Dataset ID: |
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| URI: | https://repository.cshl.edu/id/eprint/41704 |
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