Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

Weng, S; Cain, L; Comben, J; Zhang, Y; Semple, T; Alaei, S; Yoannidis, D; Martelotto, L; Mitchell, C; Pasam, A; Young, RJ; Blyth, B; Hendley, J; Feng, Y; Thorne, H; Wallace, R; Chan, J; Como, J; Devereux, L; Beltran, H; Wetterskog, D; Williams, S; Papenfuss, AT; Parker, B; Neeson, P; Attard, G; Quigley, D; Goode, DL; Pearson, RB; Furic, L; Trigos, AS; Sandhu, S

Author(s): Weng, S; Cain, L; Comben, J; Zhang, Y; Semple, T; Alaei, S; Yoannidis, D; Martelotto, L; Mitchell, C; Pasam, A; Young, RJ; Blyth, B; Hendley, J; Feng, Y; Thorne, H; Wallace, R; Chan, J; Como, J; Devereux, L; Beltran, H; Wetterskog, D; Williams, S; Papenfuss, AT; Parker, B; Neeson, P; Attard, G; Quigley, D; Goode, DL; Pearson, RB; Furic, L; Trigos, AS; Sandhu, S;
Details: Publication Year 2026-06-19,Volume 17,Issue #1,Page 7727
Journal Title: Nature Communications
Publication Type: Jun 19
Abstract: 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.
Publisher: Springer Nature
Keywords: Humans; Male; Neoplasm Metastasis/genetics; Tumor Microenvironment/genetics; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology; *Genetic Heterogeneity; Clonal Evolution/genetics; Gene Expression Regulation, Neoplastic; *Prostatic Neoplasms/genetics/pathology; Single-Cell Analysis; Whole Genome Sequencing; *Neoplasm Recurrence, Local/genetics/pathology
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 42321191
Publisher's Version: https://doi.org/10.1038/s41467-026-74334-z
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-026-74334-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-26 08:17:26

Last Modified: 2026-08-14 11:30:42