Metastatic prostate cancer (mPC) is a clinically and molecularly heterogeneous disease. While there is increasing recognition of diverse tumor phenotypes across patients, less is known about the molecular and phenotypic heterogeneity present within an individual. In this study, we aimed to define the patterns, extent, and consequences of inter- and intra-tumoral heterogeneity in lethal prostate cancer. By combining and integrating in situ tissue-based and sequencing approaches, we analyzed over 630 tumor samples from 52 mPC patients. Our efforts revealed phenotypic heterogeneity at the patient, metastasis, and cellular levels. We observed that intra-patient, inter-tumoral molecular subtype heterogeneity was common in mPC and showed associations with genomic and clinical features. Additionally, cellular proliferation rates varied within a given patient across molecular subtypes and anatomic sites. Single-cell sequencing studies revealed features of morphologically and molecularly divergent tumor cell populations within a single metastatic site. These data provide a deeper insight into the complex patterns of tumoral heterogeneity in mPC with implications for clinical management and the future development of diagnostic and therapeutic approaches.
The Journal of clinical investigation. 2025 Jun 10 [Epub ahead of print]
Martine P Roudier, Roman Gulati, Erolcan Sayar, Radhika A Patel, Micah Tratt, Helen M Richards, Paloma Cejas, Miguel Munoz Gomez, Xintao Qiu, Yingtian Xie, Brian Hanratty, Samir Zaidi, Jimmy L Zhao, Mohamed Adil, Chitvan Mittal, Yibai Zhao, Ruth Dumpit, Ilsa Coleman, Jin-Yih Low, Thomas Persse, Patricia C Galipeau, John K Lee, Maria Tretiakova, Meagan Chambers, Funda Vakar-Lopez, Lawrence D True, Marie Perrone, Hung-Ming Lam, Lori A Kollath, Chien-Kuang C Ding, Stephanie Harmon, Heather H Cheng, Evan Y Yu, Robert B Montgomery, Jessica E Hawley, Daniel W Lin, Eva Corey, Michael T Schweizer, Manu Setty, Gavin Ha, Charles L Sawyers, Colm Morrissey, Henry W Long, Peter S Nelson, Michael C Haffner
Department of Urology, University of Washington, Seattle, United States of America., Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America., Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America., Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America., Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America., Oncology R&D, Astrazeneca, New York, United States of America., Division of Human Biology, University of Washington, Seattle, United States of America., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America., Department of Anatomic Pathology, UCSF, San Francisco, United States of America., Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America., Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America.