Single‐cell transcriptomics redefines focal neuroendocrine differentiation as a distinct prostate cancer pathology
Neuroendocrine prostate cancer (NEPC) tumours are classified by pathology into several distinct subtypes. Gene expression profiling has revealed transcriptional heterogeneity across NEPC, but this is rarely considered in the context of variation between pathologies. Diagnosis typically relies on immunohistochemical markers (CHGA, SYP, NCAM1) and genomic alterations in RB1, PTEN and TP53. We hypothesized that NEPC pathologies have unique transcriptional features. Single-cell RNA sequencing of 18 632 tumour cells from nine patient-derived xenograft models representing five pathologies (small-cell and large-cell neuroendocrine carcinomas, focal neuroendocrine differentiation (Focal NED), low-grade neuroendocrine and amphicrine) demonstrated pathway-specific enrichment. Focal NED and amphicrine tumours exhibited cellular subpopulations enriched for KRAS, IL2-STAT5 and TNF signalling pathways, absent in small- and large-cell carcinomas, which were instead enriched for Myc and E2F pathways. Furthermore, focal NED cells exhibited minimal clonal divergence from adjacent adenocarcinoma cells, while small cell carcinoma cells were clonally distinct. These data underscore significant transcriptional variation among NEPC pathologies, highlighting focal NED's unique biological context and its clinical implications.
Authors
- Rosalía Quezada Urban (ORCID: https://orcid.org/0000-0002-1486-9116)
- Mitchell G. Lawrence (ORCID: https://orcid.org/0000-0001-9520-3000)
- Andrew Bakshi (ORCID: https://orcid.org/0000-0001-5650-7036)
- Belinda Phipson (ORCID: https://orcid.org/0000-0002-1711-7454)
- David L. Goode (ORCID: https://orcid.org/0000-0002-3277-6562)
- Roxanne Toivanen (ORCID: https://orcid.org/0000-0002-5765-9346)
- Shivakumar Keerthikumar (ORCID: https://orcid.org/0000-0001-9865-9767)
- Andrew Ryan (ORCID: https://orcid.org/0000-0002-5337-4714)
- Renea A. Taylor (ORCID: https://orcid.org/0000-0003-2609-2380)
- Gail P. Risbridger (ORCID: https://orcid.org/0000-0003-3089-4028)
- Hong Wang (ORCID: https://orcid.org/0000-0003-3524-0891)
- Heather Thorne (ORCID: https://orcid.org/0000-0003-3610-2511)
- Ashlee Clark
Institutions
- The University of Melbourne (AU)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Discovery Institute (US)
- Peter MacCallum Cancer Centre (AU)
- Cabrini Hospital (AU)
- TissuPath (AU)
- Monash University (AU)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1002/1878-0261.70099
- Citations
- 1
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.52
Funders
- Victorian Cancer Agency
- Movember Foundation
- National Breast Cancer Foundation
- Cass Foundation
- Cancer Australia
- Monash University
- Peter MacCallum Cancer Centre
- Peter MacCallum Foundation
- National Health and Medical Research Council
- Cancer Council Victoria
- Sistema Nacional de Investigadores