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 6

Inter- and intratumoral heterogeneity at the single-patient level.

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Inter- and intratumoral heterogeneity at the single-patient level. (A) S...
(A) Schematic of analyzed metastatic sites and phenotype distribution in patient 13-084. (B) Representative micrographs of 5 lesions demonstrating the spectrum of histomorphological and molecular heterogeneity across different tumor sites. (C) Somatic copy number profiles derived from WGS demonstrating overlapping copy number changes and limited genomic diversity across phenotypically diverse metastases. Shared copy number changes in key genomic regions are highlighted in yellow. (D) Histomorphologic assessment of a prostatic/periprostatic tumor mass shows adjacent AR+/NE– adenocarcinoma (ARPC), AR–/NE+ small-cell carcinoma (NEPC), and AR–/NE– sarcomatoid carcinoma (SARC). (E) UMAP based on snATAC-seq data demonstrating 4 tumor cell clusters based on chromatin accessibility pattern and highlighting 2 distinct NEPC clusters that are characterized by ASCL1 (NEPC-A) and NEUROD1 (NEPC-N) expression (both AR–/NE+). (F) Bubble plots showing cluster-specific gene expression pattern based on snRNA-seq. Scale bars: 50 μm.