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.
Nature communications. 2026 Jun 19 [Epub ahead of print]
Sirui Weng, Lachlan Cain, James Comben, Yangyi Zhang, Timothy Semple, Sara Alaei, David Yoannidis, Luciano Martelotto, Catherine Mitchell, Anupama Pasam, Richard J Young, Benjamin Blyth, Joy Hendley, Yuzhou Feng, Heather Thorne, Roslyn Wallace, Joanna Chan, Julia Como, Lisa Devereux, Himisha Beltran, Daniel Wetterskog, Scott Williams, Anthony T Papenfuss, Belinda Parker, Paul Neeson, Gerhardt Attard, David Quigley, David L Goode, Richard B Pearson, Luc Furic, Anna S Trigos, Shahneen Sandhu
Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., St. Vincent's Institute of Medical Research, Fitzroy, VIC, Australia., Adelaide Centre for Epigenetics, The University of Adelaide, Adelaide, SA, Australia., Department of Clinical Pathology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, VIC, Australia., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., University College London Cancer Institute, London, UK., The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., Department of Urology, University of California San Francisco, San Francisco, CA, USA., Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. ., Peter MacCallum Cancer Centre, Melbourne, VIC, Australia. .