Patterns of intra- and intertumor phenotypic heterogeneity in lethal prostate cancer
Martine P. Roudier, et al.
Martine P. Roudier, et al.
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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 4

Clinical features associated with molecular subtypes and intrapatient heterogeneity.

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Clinical features associated with molecular subtypes and intrapatient he...
(A) Clinical trajectories for 52 patients included in this study. Bars showing the time from initial diagnosis to death for each patient and are color coded in light blue to indicate the interval from diagnosis to start of androgen deprivation therapy (ADT) and gray for the period after ADT initiation. M indicates the time of first bone metastasis; R indicates first clinical evidence of resistance to ADT. The asterisk indicates that this patient did not receive ADT. Patients are sorted based on dominant molecular subtype (green, AR+/NE–; yellow, AR–/NE+; red, AR+/NE+; and blue, AR–/NE–) and the HI (gray scale heatmap). (B) Summary of prior therapies. Stacked bar graphs showing the number of patients that have (dark color) or have not (light color) received the indicated systemic therapies (abiraterone acetate, enzalutamide, and taxane- and platinum-based chemotherapies) as a function of the dominant molecular subtype. (C) Last recorded PSA serum levels for each patient broken down by dominant molecular subtype. (D) Box plots showing time intervals from first bone metastasis to death for patients with no NE marker positivity compared with patients with any NE marker positivity (INSM1 or SYP H-score ≥ 20). P value was derived using the Wilcox-Mann-Whitney test. (E) Box plot showing time from bone metastasis to death across all 52 patients stratified by dominant molecular subtype. P value was derived using the Kruskal-Wallis test. (F) Time interval from time from bone metastasis to death in patients with a HI of greater than 50% or below. Note that corresponding analyses for other time intervals, diagnosis to death, and ADT to death are shown in Supplemental Figure 5D. In box plots, horizontal bars indicate the medians and boxes indicate 25th to 75th percentiles.