The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1
The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1
ABSTRACT Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and characterize the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e.g., Rb1-/-; Trp53-/-; cMyc+ or Pten-/-; Trp53-/-; cMyc+), but only those with Rb1 deletion progress to ASCL1+ neuroendocrine prostate cancer (NEPC), a highly aggressive, androgen receptor signaling inhibitor (ARSI)-resistant tumor. Importantly, we show this lineage transition requires a native in vivo microenvironment not replicated by conventional organoid culture. By integrating multiplex immunofluorescence, spatial transcriptomics and PrismSpot to identify cell type-specific spatial gene modules, we reveal that ASCL1+ cells arise from KRT8+ luminal epithelial cells that progressively acquire transcriptional heterogeneity, producing large ASCL1+/KRT8- NEPC clusters. Ascl1 loss in established NEPC results in transient tumor regression followed by recurrence; however, Ascl1 deletion prior to transplantation completely abrogates lineage plasticity, yielding adenocarcinomas with elevated AR expression and marked sensitivity to castration. The dynamic feature of this model reveals the importance of timing of therapies focused on lineage plasticity and offers a platform for identification of additional lineage plasticity drivers.
Lawrence Kayla E.、Smith Perianne、Westcott Peter M.K.、Mao Chenyi、Gerstner Olivia、Kaur Harmanpreet、Kang Wenfei、Pulina Maria V.、Xie Yubin、Chalign¨| Ronan、Zaidi Samir、Yoo Kwangmin、Fan Ning、Karthaus Wouter R.、Romero Rodrigo、Gonz¨￠lez-Robles Tania J.、Zhao Huiyong、DeStanchina Elisa、Gopalan Anuradha、Pe?ˉer Dana、Sawyers Charles L.、Choi Jungmin、Chu Tinyi、Ruggles Kelly V.、Yoder Sara
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterCold Spring Harbor Laboratory, Cold Spring HarborMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer CenterMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer CenterProgram for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterProgram for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center||Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center||Department of Genitourinary Oncology, Memorial Sloan Kettering Cancer CenterDepartment of Biomedical Sciences, Korea University College of MedicineMolecular Cytology Core Facility, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterInstitute of Systems Genetics, Department of Precision Medicine, NYU Grossman School of Medicine||Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of MedicineAntitumor Assessment Core Facility, Memorial Sloan Kettering Cancer CenterAntitumor Assessment Core Facility, Memorial Sloan Kettering Cancer CenterHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer CenterProgram for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center||Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center||Howard Hughes Medical InstituteHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center||Howard Hughes Medical InstituteDepartment of Biomedical Sciences, Korea University College of MedicineProgram for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer CenterInstitute of Systems Genetics, Department of Precision Medicine, NYU Grossman School of MedicineDepartment of Pathology, Memorial Sloan Kettering Cancer Center
肿瘤学基础医学分子生物学
Lawrence Kayla E.,Smith Perianne,Westcott Peter M.K.,Mao Chenyi,Gerstner Olivia,Kaur Harmanpreet,Kang Wenfei,Pulina Maria V.,Xie Yubin,Chalign¨| Ronan,Zaidi Samir,Yoo Kwangmin,Fan Ning,Karthaus Wouter R.,Romero Rodrigo,Gonz¨￠lez-Robles Tania J.,Zhao Huiyong,DeStanchina Elisa,Gopalan Anuradha,Pe?ˉer Dana,Sawyers Charles L.,Choi Jungmin,Chu Tinyi,Ruggles Kelly V.,Yoder Sara.The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2024.04.09.588557.点此复制
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