A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors
- Columbia University Medical Center, United States
- Weill Cornell Medical Center, United States
Abstract
Understanding the cellular constituents of the prostate is essential for identifying the cell of origin for prostate adenocarcinoma. Here we describe a comprehensive single-cell atlas of the adult mouse prostate epithelium, which displays extensive heterogeneity. We observe distal lobe-specific luminal epithelial populations (LumA, LumD, LumL, and LumV), a proximally-enriched luminal population (LumP) that is not lobe-specific, and a periurethral population (PrU) that shares both basal and luminal features. Functional analyses suggest that LumP and PrU cells have multipotent progenitor activity in organoid formation and tissue reconstitution assays. Furthermore, we show that mouse distal and proximal luminal cells are most similar to human acinar and ductal populations, that a PrU-like population is conserved between species, and that the mouse lateral prostate is most similar to the human peripheral zone. Our findings elucidate new prostate epithelial progenitors, and help resolve long-standing questions about anatomical relationships between the mouse and human prostate.
Data availability
Single-cell RNA-sequencing data from this study have been deposited in the Gene Expression Omnibus (GEO) under the accession number GSE150692, and can also be accessed through the Broad Institute Single-Cell Portal (www.singlecell.broadinstitute.org).
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Single-cell RNA-seq analysis of mouse and human prostateNCBI Gene Expression Omnibus, GSE150692.
Article and author information
Author details
Funding
National Cancer Institute (R01CA238005)
- Michael M Shen
National Cancer Institute (U54CA193313)
- Raul Rabadan
- Michael M Shen
National Cancer Institute (P50CA211024)
- Massimo Loda
- Michael M Shen
National Cancer Institute (K99CA194287)
- Maho Shibata
T.J. Martell Foundation
- Michael M Shen
Department of Defense Prostate Cancer Research Program (W81XWH-18-1-0424)
- Francesco Cambuli
National Science Foundation
- Laura Crowley
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were conducted according to protocols (AC-AABE0556, AC-AABG0564, AC-AABE5557) approved by the Columbia University Irving Medical Center (CUIMC) Institutional Animal Care and Use Committee (IACUC).
Human subjects: Human prostate tissue specimens were obtained from patients undergoing cystoprostatectomy for bladder cancer or radical prostatectomy at Columbia University Irving Medical Center or at Weill Cornell Medicine. Patients gave informed consent under an Institutional Review Board-approved protocol (AAAN8850).
Copyright
© 2020, Crowley et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A single-cell atlas of the mouse and human prostate reveals heterogeneity and conservation of epithelial progenitors
eLife 9:e59465.
https://doi.org/10.7554/eLife.59465
Further reading
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In this study, we present a proof-of-concept classical vaccination experiment that validates the in silico identification of tumor neoantigens (TNAs) using a machine learning-based platform called NAP-CNB. Unlike other TNA predictors, NAP-CNB leverages RNA-seq data to consider the relative expression of neoantigens in tumors. Our experiments show the efficacy of NAP-CNB. Predicted TNAs elicited potent antitumor responses in mice following classical vaccination protocols. Notably, optimal antitumor activity was observed when targeting the antigen with higher expression in the tumor, which was not the most immunogenic. Additionally, the vaccination combining different neoantigens resulted in vastly improved responses compared to each one individually, showing the worth of multiantigen-based approaches. These findings validate NAP-CNB as an innovative TNA identification platform and make a substantial contribution to advancing the next generation of personalized immunotherapies.
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- Cancer Biology
Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
