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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 13, 2022
- Source ID
- 10.7554/elife.79076
Entities
People
- Adam G Sowalsky
- Alexandre A Germanos
- Andrew C Hsieh
- Annalysa Long
- Anson T. Ku
- Cyrus M Ghajar
- David S. Rickman
- Erica T Goddard
- Franklin W. Huang
- Hanbing Song
- Ilsa M. Coleman
- Jason H. Bielas
- Manu Setty
- Michael A Zager
- Nicholas J. Brady
- Peter S Nelson
- Raphael Gottardo
- Robert A Amezquita
- Scott Wilkinson
- Sonali Arora
- Ye Zheng
- Yu Chi Yang
Organizations
- Burroughs Wellcome Fund
- Emerson Collective
- Fred Hutchinson Cancer Center
- National Cancer Institute
- National Institute of General Medical Sciences
- Prostate Cancer Foundation
- Robert J Kleberg Jr and Helen C Kleberg Foundation
- United States Department of Defense
- University of California, San Francisco
- University of Washington
- Weill Cornell Medicine