Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer
The evolution to metastatic disease is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic heterogeneity in late-stage disease, we focus on metastatic castration-resistant prostate cancer and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions obtained from 9 patients through rapid autopsy. We find evolutionary convergence of intra-tumour heterogeneity, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. We find little evidence of the microenvironment driving transcriptional heterogeneity, but there are signatures of co-adaptation between the microenvironment and tumour cells. In contrast, clonal evolution primarily foster widespread transcriptional changes that did not result in de novo functional states. Intra-patient functional convergence of tumour ecosystems across metastases indicates system-level selection pressures that drive the heterogeneity landscape of metastatic castration-resistant prostate cancer. Our findings reveal functional evolutionary convergence of metastatic disease into distinct intra-tumour subpopulations, identifying critical determinants for therapeutic targeting.
Authors
- Gerhardt Attard (ORCID: https://orcid.org/0000-0002-4811-7983)
- Lisa Devereux (ORCID: https://orcid.org/0000-0003-2435-5888)
- Richard B. Pearson (ORCID: https://orcid.org/0000-0001-5919-5090)
- Luc Furic (ORCID: https://orcid.org/0000-0002-1893-9812)
- Y. C. Zhang
- Timothy Semple (ORCID: https://orcid.org/0000-0002-4048-1553)
- Luciano G. Martelotto (ORCID: https://orcid.org/0000-0002-9625-1183)
- Catherine Mitchell (ORCID: https://orcid.org/0000-0001-5596-9511)
- Paul J. Neeson (ORCID: https://orcid.org/0000-0002-2729-5887)
- Anna Trigos (ORCID: https://orcid.org/0000-0002-5915-2952)
- David L. Goode (ORCID: https://orcid.org/0000-0002-3277-6562)
- David A. Quigley (ORCID: https://orcid.org/0000-0002-4726-1473)
- Belinda S. Parker (ORCID: https://orcid.org/0000-0002-8333-1926)
- Roslyn Wallace
- Yuzhou Feng (ORCID: https://orcid.org/0000-0002-2955-4053)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- David Yoannidis (ORCID: https://orcid.org/0000-0001-9591-1349)
- Joy Hendley (ORCID: https://orcid.org/0009-0004-8779-6757)
- Anthony T. Papenfuss (ORCID: https://orcid.org/0000-0002-1102-8506)
- Julia Como (ORCID: https://orcid.org/0000-0003-0620-9457)
- Shahneen Kaur Sandhu (ORCID: https://orcid.org/0000-0002-8660-4475)
- Daniel Wetterskog (ORCID: https://orcid.org/0000-0003-4163-6438)
- Anupama Pasam
- Richard J. Young
- James Comben
- B. Blyth
- Sara Alaei
- Scott Williams
- Sirui Weng
- Joanna Chan
- Heather Thorne
- Lachlan Cain
Institutions
- Harvard University (US)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- Walter and Eliza Hall Institute of Medical Research (AU)
- Peter MacCallum Cancer Centre (AU)
- Australian Regenerative Medicine Institute (AU)
- London Cancer (GB)
- Dana-Farber Cancer Institute (US)
- Centre for Cancer Biology (AU)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- University College London (GB)
- Monash University (AU)
- The University of Adelaide (AU)
- St Vincents Institute of Medical Research (AU)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-19
- DOI
- https://doi.org/10.1038/s41467-026-74334-z
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- National Health and Medical Research Council