Evolution and heterogeneity of lethal metastatic bladder cancer subtypes

Histological variation is a prognostic feature of metastatic urothelial cancer1–3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes. A rapid autopsy programme provides valuable resources to enable detailed molecular and genetic analyses of the temporal evolution of aggressive histological subtypes and therapy resistance in metastatic bladder cancer.

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Publication Details

Journal
Nature
Published
2026-09-16
DOI
https://doi.org/10.1038/s41586-026-11035-z
Primary Topic
Bladder and Urothelial Cancer Treatments
Type
article
Field-Weighted Citation Impact
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article

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes

Andrew C. Hsieh, Omar Y. Mian, Jessica E. Hawley, Dmytro Rudoy et al.
Nature
Bladder and Urothelial Cancer Treatments
article

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes

Andrew C. Hsieh, Omar Y. Mian, Jessica E. Hawley, Dmytro Rudoy, Hung‐Ming Lam, Eva Corey, Erolcan Sayar, Samantha L. Schuster, Petros Grivas, Patricia C. Galipeau, Manasvita Vashisth, Gavin Ha, Robert D. Patton, Michael Yang, Todd Yezefski, Minjeong Ko, John K. Lee, Peter S. Nelson, M. Schweizer, Lawrence Fong, Allie Kreitman, Pushpa Itagi, Sonali Arora, Sarah P. Psutka, Thomas Persse, Khursheed Ali, Jonathan Wright, Claire B. Mills, Jin Yeong kim, Daniel W. Lin, Lori Kollath, Evan Y. Yu, Robert B. Montgomery, Cynthia L. Wladyka, Colm Morrissey, Nathan Ji, Funda Vakar-Lopez, John L. Gore, Heather H. Cheng, Samuel Lindergren, Mohamed Adil, Michael C. Haffner, Abby Meis, A. Patrick McDeed, Rosa Nadal, Pooja Chandra, Hrishi Venkatesh, Jennifer A. Waters, Yixin Lin, Alan Min
article en

Abstract

Histological variation is a prognostic feature of metastatic urothelial cancer1–3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes. A rapid autopsy programme provides valuable resources to enable detailed molecular and genetic analyses of the temporal evolution of aggressive histological subtypes and therapy resistance in metastatic bladder cancer.

Nature
University of California, Los Angeles (US), University of Washington (US), Fred Hutch Cancer Center (US)
No poverty
Openalex Percentile: Top 8%
Bladder and Urothelial Cancer Treatments
DOIOpen Access PDFOpenAlex
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