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

TitleDefining cellular population dynamics at single-cell resolution during prostate cancer progression.
Publication TypeJournal Article
Year of Publication2022
AuthorsGermanos AA, Arora S, Zheng Y, Goddard ET, Coleman IM, Ku AT, Wilkinson S, Song H, Brady NJ, Amezquita RA, Zager M, Long A, Yang YChi, Bielas JH, Gottardo R, Rickman DS, Huang FW, Ghajar CM, Nelson PS, Sowalsky AG, Setty M, Hsieh AC
JournalElife
Volume11
Date Published2022 Dec 13
ISSN2050-084X
KeywordsAndrogens, Animals, Disease Progression, Humans, Male, Mice, Orchiectomy, Population Dynamics, Prostate, Prostatic Neoplasms, Receptors, Androgen, Tumor Microenvironment
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.

DOI10.7554/eLife.79076
Alternate JournalElife
PubMed ID36511483
PubMed Central IDPMC9747158
Grant ListP30 CA015704 / CA / NCI NIH HHS / United States
S10 OD028685 / CA / NCI NIH HHS / United States
R01 CA234715 / CA / NCI NIH HHS / United States
P50 CA097186 / CA / NCI NIH HHS / United States
P01 CA163227 / CA / NCI NIH HHS / United States
R01 GM135362 / GM / NIGMS NIH HHS / United States
R37 CA230617 / CA / NCI NIH HHS / United States
T32 CA080416 / CA / NCI NIH HHS / United States
Related Faculty: 
Nicholas Brady, Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700