Prostate Cancer Treatment and Research
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Peer reviewed
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A versatile in vivo platform to identify and characterize the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression, and shows this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture.
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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.
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@article{Romero2024neuroendocrine,
title = {The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1},
author = {Rodrigo Romero and Tinyi Chu and Tania J González-Robles and Perianne Smith and Yubin Xie and Harmanpreet Kaur and Sara Yoder and Huiyong Zhao and Chenyi Mao and Wenfei Kang and Maria V. Pulina and Kayla E. Lawrence and Anuradha Gopalan and Samir Zaidi and Kwangmin Yoo and Jungmin Choi and Ning Fan and Olivia Gerstner and Wouter R. Karthaus and Elisa DeStanchina and Kelly V. Ruggles and Peter M.K. Westcott and Ronan Chaligné and Dana Pe’er and Charles L. Sawyers},
journal = {Nature Cancer},
year = {2024},
doi = {10.1038/s43018-024-00838-6},
url = {https://doi.org/10.1038/s43018-024-00838-6}
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