Dataset Information

Defining cellular population dynamics at single-cell resolution during prostate cancer progression.

ABSTRACT: Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity, which is inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition, which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.

SUBMITTER: Germanos AA

PROVIDER: S-EPMC9747158 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Defining cellular population dynamics at single-cell resolution during prostate cancer progression.

Germanos Alexandre A AA Arora Sonali S Zheng Ye Y Goddard Erica T ET Coleman Ilsa M IM Ku Anson T AT Wilkinson Scott S Song Hanbing H Brady Nicholas J NJ Amezquita Robert A RA Zager Michael M Long Annalysa A Yang Yu Chi YC Bielas Jason H JH Gottardo Raphael R Rickman David S DS Huang Franklin W FW Ghajar Cyrus M CM Nelson Peter S PS Sowalsky Adam G AG Setty Manu M Hsieh Andrew C AC

eLife 20221213

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. ...[more]

PMID: 36511483

Similar Datasets

Project description:Advanced prostate cancer is a leading cause of cancer-related deaths in men, in large part due to our poor understanding of advanced castration-resistant prostate cancer (CRPC). This form of prostate cancer is uniformly lethal. Currently, the main treatments against this disease are anti-androgenic therapies; however, CRPC always develops resistance to these therapeutic modalities. Of particular interest is CRPC lacking androgen receptor (AR) activity, or AR-low CRPC. This subtype has dramatically increased in incidence in the past decade. While many studies have identified a complex architecture in the prostate, we still lack a unified view of the cellular interactions and phenotypes that facilitate advanced prostate cancer maintenance and survival, particularly without AR signaling.To better understand the cellular changes that drive CRPC, we harvested prostates from a mouse model of prostate cancer under multiple conditions and performed single-cell RNA sequencing (scRNASeq). Our findings reveal a subset of the epithelial compartment that is primed for AR-low survival during tumorigenesis, as well as a complex basal-driven mechanism to facilitate expansion of this subtype. Androgen deprivation via castration of the mouse modulates this process by increasing proliferation rates in epithelia. In addition, we observe a dramatic increase in immune cell population upon tumorigenesis. We identify this immune influx as pro-tumor and pinpoint unique signaling phenotypes from individual epithelial subtypes, demonstrating a multifaceted process of recruitment and remodeling by the tumor to build a favorable environment. Androgen signaling is also crucial for maintaining these immune populations, and castration dramatically remodels the tumor environment. Finally, we uncover the importance of protein synthesis regulation in maintaining these complex dynamics; inhibiting the eIF4F translation initiation complex leads to decreased epithelial proliferation and immune recruitment. These findings shed new light on the cellular dynamics of advanced prostate cancer and highlight the importance of employing high-throughput technologies to provide a complete picture of the tumor and its microenvironment. Better understanding of the epithelial subtypes involved in tumor growth, as well as their influence on immune populations in the prostate, can lead to new avenues of treatment.

Dataset Information

Defining cellular population dynamics at single-cell resolution during prostate cancer progression.

Publications

Defining cellular population dynamics at single-cell resolution during prostate cancer progression.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets