Title | Defining cellular population dynamics at single-cell resolution during prostate cancer progression. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Germanos 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 |
Journal | Elife |
Volume | 11 |
Date Published | 2022 Dec 13 |
ISSN | 2050-084X |
Keywords | Androgens, 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. |
DOI | 10.7554/eLife.79076 |
Alternate Journal | Elife |
PubMed ID | 36511483 |
PubMed Central ID | PMC9747158 |
Grant List | P30 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.