Patterns of intra- and intertumor phenotypic heterogeneity in lethal prostate cancer
Martine P. Roudier, … , Peter S. Nelson, Michael C. Haffner
Martine P. Roudier, … , Peter S. Nelson, Michael C. Haffner
Published June 10, 2025
Citation Information: J Clin Invest. 2025;135(15):e186599. https://doi.org/10.1172/JCI186599.
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Research Article Cell biology Oncology

Patterns of intra- and intertumor phenotypic heterogeneity in lethal prostate cancer

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 intratumoral heterogeneity in lethal prostate cancer. By combining and integrating in situ tissue-based and sequencing approaches, we analyzed over 630 tumor samples from 52 patients with mPC. Our efforts revealed phenotypic heterogeneity at the patient, metastasis, and cellular levels. We observed that intrapatient intertumoral 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.

Authors

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 Galipeau, John K. Lee, Maria Tretiakova, Meagan Chambers, Funda Vakar-Lopez, Lawrence D. True, Marie Perrone, Hung-Ming Lam, Lori A. Kollath, Chien-Kuang Cornelia 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 Long, Peter S. Nelson, Michael C. Haffner

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Figure 2

Patterns of subtype heterogeneity and association with genomic alterations.

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Patterns of subtype heterogeneity and association with genomic alteratio...
(A) Summary of individual sample-level and integrated patient-level assessments of molecular subtypes and subtype heterogeneity, using patient 15-010 as an example. (B) Pie chart shows number and percentages of patients with homogenous and heterogeneous molecular subtype distribution. UpSet plot shows the patterns of molecular subtype co-occurrence across all metastatic sites in 52 patients. (C) HI distributions across different dominant molecular subtypes. P values were derived using the Wilcox-Mann-Whitney test. (D) Comutation plot depicting molecular subtype and genomic features of patients included in the study. Each column represents a patient (case IDs are listed at the bottom). Rows show from top to bottom: IHC-derived dominant molecular subtype (defined as the most commonly observed subtype across all metastases); IHC-derived subtype contribution for each of the four subtypes (AR+/NE–, AR–/NE–, AR+/NE+, and AR–/NE–) (heatmap scaled 0–1) shown as the relative fraction of tumor samples from each subtype in a patient; HI (shown as a heatmap scaled 0–100); whole-exome sequencing–derived key genomic alterations (AR, PTEN, RB1, CHD1, TP53, and BRCA2) shared across all metastases (see legend to the left for alteration type). Asterisks indicate no genomic data are available. CN, copy number. (E) Mosaic plots illustrating the relative distributions of molecular subtypes (along the x axis) and the associated relative distributions of genomic alterations (along the y axis) (see Supplemental Table 4 for details). Dark colors indicate the presence of a given genomic alteration, and light colors show absence. Plots are scaled to the total number of samples in each molecular subtype. (F) HIs for AR and PTEN altered and WT patients. P values were derived using the Wilcox-Mann-Whitney test. (G) Estimated median differences and 95% CIs of HIs between patients with (altered) and without (unaltered) indicated gene alterations (HIaltered – HIunaltered). Numbers in parentheses represent the number of patients, with the first number indicating altered cases.