The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 Journal Article
| Authors: | Romero, R.; Chu, T.; González Robles, T. J.; Smith, P.; Xie, Y.; Kaur, H.; Yoder, S.; Zhao, H.; Mao, C.; Kang, W.; Pulina, M. V.; Lawrence, K. E.; Gopalan, A.; Zaidi, S.; Yoo, K.; Choi, J.; Fan, N.; Gerstner, O.; Karthaus, W. R.; DeStanchina, E.; Ruggles, K. V.; Westcott, P. M. K.; Chaligné, R.; Pe’er, D.; Sawyers, C. L. |
| Article Title: | The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1 |
| 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. © The Author(s) 2024. |
| Keywords: | human tissue; overall survival; nonhuman; flow cytometry; nuclear magnetic resonance imaging; quality control; mouse; gene expression; confocal microscopy; cell infiltration; animal experiment; lung cancer; transcription factor; transcriptomics; enzyme linked immunosorbent assay; docetaxel; prostate cancer; regulatory t lymphocyte; prostatectomy; carcinogenicity; electroporation; androgen receptor; castration; testosterone blood level; doxycycline; analysis of variance; androgen deprivation therapy; nerve cell differentiation; fluorescence activated cell sorting; degarelix; testosterone; student t test; downstream processing; cancer transplantation; synaptophysin; tumor microenvironment; meloxicam; buprenorphine; orthotopic transplantation; chondrocyte; transcription factor mash1; ultracentrifugation; enzalutamide; human; male; article; organoid; gene editing; neuroendocrine regulation |
| Journal Title: | Nature Cancer |
| Volume: | 5 |
| Issue: | 11 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2024-11-01 |
| Start Page: | 1641 |
| End Page: | 1659 |
| Language: | English |
| DOI: | 10.1038/s43018-024-00838-6 |
| PUBMED: | 39394434 |
| PROVIDER: | scopus |
| PMCID: | PMC11584404 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Charles L. Sawyers -- Source: Scopus |
