Defining cellular population dynamics at single-cell resolution during prostate cancer progression.
Alexandre A GermanosSonali AroraYe ZhengErica T GoddardIlsa M ColemanAnson T KuScott WilkinsonHanbing SongNicholas J BradyRobert A AmezquitaMichael A ZagerAnnalysa LongYu Chi YangJason H BielasRaphael GottardoDavid S RickmanFranklin W HuangCyrus M GhajarPeter S NelsonAdam G SowalskyManu SettyAndrew C HsiehPublished in: eLife (2022)
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.
Keyphrases
- single cell
- prostate cancer
- poor prognosis
- rna seq
- radical prostatectomy
- cell death
- high throughput
- long non coding rna
- cell cycle arrest
- end stage renal disease
- induced apoptosis
- ejection fraction
- newly diagnosed
- endothelial cells
- single molecule
- stem cells
- anti inflammatory
- prognostic factors
- chronic kidney disease
- signaling pathway
- peritoneal dialysis
- gene expression
- genome wide
- cell proliferation
- extracellular matrix
- oxidative stress
- dna methylation
- mesenchymal stem cells
- bone marrow
- combination therapy
- pi k akt
- pluripotent stem cells
- binding protein