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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI186599

Patterns of intra- and inter-tumor phenotypic heterogeneity in lethal prostate cancer

Martine P. Roudier,1 Roman Gulati,2 Erolcan Sayar,3 Radhika A. Patel,3 Micah Tratt,3 Helen M. Richards,3 Paloma Cejas,4 Miguel Munoz Gomez,4 Xintao Qiu,4 Yingtian Xie,4 Brian Hanratty,3 Samir Zaidi,5 Jimmy L. Zhao,6 Mohamed Adil,7 Chitvan Mittal,3 Yibai Zhao,2 Ruth Dumpit,3 Ilsa Coleman,3 Jin-Yih Low,3 Thomas Persse,2 Patricia C. Galipeau,2 John K. Lee,3 Maria Tretiakova,9 Meagan Chambers,9 Funda Vakar-Lopez,9 Lawrence D. True,9 Marie Perrone,9 Hung-Ming Lam,1 Lori A. Kollath,1 Chien-Kuang C. Ding,10 Stephanie Harmon,11 Heather H. Cheng,12 Evan Y. Yu,12 Robert B. Montgomery,12 Jessica E. Hawley,12 Daniel W. Lin,1 Eva Corey,1 Michael T. Schweizer,12 Manu Setty,2 Gavin Ha,2 Charles L. Sawyers,14 Colm Morrissey,1 Henry W. Long,4 Peter S. Nelson,1 and Michael C. Haffner3

1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Department of Urology, University of Washington, Seattle, United States of America

2Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seatte, United States of America

3Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, United States of America

4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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4Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, United States of America

5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

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7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

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5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

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5Center of Molecular and Cellular Oncology, Yale Cancer Center, New Haven, United States of America

6Oncology R&D, Astrazeneca, New York, United States of America

7Division of Human Biology, University of Washington, Seattle, United States of America

8Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, United States of America

9Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States of America

10Department of Anatomic Pathology, UCSF, San Francisco, United States of America

11Molecular Imaging Program, National Cancer Institute, NIH, Bethesda, United States of America

12Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, United States of America

13Department of Urology, University of Washington, Settle, United States of America

14Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

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Published June 10, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI186599.
Copyright © 2025, Roudier et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 10, 2025 - Version history
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Abstract

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.

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