The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1
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<sup>-/-</sup>; Trp53<sup>-/-</sup>; cMyc<sup>+</sup> or Pten<sup>-/-</sup>; Trp53<sup>-/-</sup>; cMyc<sup>+</sup>) develop adenocarcinomas, but only those with Rb1 deletion advance to aggressive, ASCL1<sup>+</sup> 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<sup>+</sup> cells arise from KRT8<sup>+</sup> luminal cells, progressing into transcriptionally heterogeneous ASCL1<sup>+</sup>;KRT8<sup>-</sup> 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.
Authors
- Harmanpreet Kaur (ORCID: https://orcid.org/0000-0002-0336-3830)
- Peter M.K. Westcott (ORCID: https://orcid.org/0000-0001-9436-4857)
- Wouter R. Karthaus (ORCID: https://orcid.org/0000-0002-9234-9044)
- Anuradha Gopalan (ORCID: https://orcid.org/0009-0007-6017-0991)
- Chenyi Mao (ORCID: https://orcid.org/0000-0002-6444-6955)
- Kelly V. Ruggles (ORCID: https://orcid.org/0000-0002-0152-0863)
- Maria V. Pulina
- Charles L. Sawyers (ORCID: https://orcid.org/0000-0003-4955-6475)
- Yubin Xie (ORCID: https://orcid.org/0000-0003-2542-2544)
- Tania J González-Robles (ORCID: https://orcid.org/0000-0001-9292-382X)
- Kayla E. Lawrence (ORCID: https://orcid.org/0000-0001-9716-7955)
- Rodrigo Romero (ORCID: https://orcid.org/0000-0002-9388-8306)
- Wenfei Kang
- Perianne Smith
- Dana Pe’er (ORCID: https://orcid.org/0000-0002-9259-8817)
- Tinyi Chu (ORCID: https://orcid.org/0000-0003-3369-6692)
- Ronan Chaligné (ORCID: https://orcid.org/0000-0003-4332-3291)
- Jungmin Choi (ORCID: https://orcid.org/0000-0002-8614-0973)
- Samir Zaidi
- Olivia Gerstner
- Huiyong Zhao (ORCID: https://orcid.org/0000-0003-4805-6858)
- Ning Fan
- Kwangmin Yoo
- Sara Yoder
- Elisa DeStanchina
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Korea University (KR)
- Cold Spring Harbor Laboratory (US)
- Institute for Systems Biology (US)
- New York University (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1038/s43018-024-00838-6
- Citations
- 43
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 18.01
Funders
- Howard Hughes Medical Institute
- Burroughs Wellcome Fund
- Damon Runyon Cancer Research Foundation
- Charles H. Revson Foundation
- National Cancer Institute