Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.
Jason S KirkJie WangAmanda TraczMark LongSpencer R RosarioYibing JiRahul KumarXiaozhuo LiuPrashant K SinghIgor PuzanovGurkamal ChattaQing ChengJiaoti HuangJeffrey L WranaJonathan LovellHan YuSong LiuMichael M ShenTao LiuDean G TangPublished in: bioRxiv : the preprint server for biology (2023)
Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas better suited to interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides chromatin context, which, when coupled with mouse lineage tracing demonstrates that the castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate JUN/FOS, WNT/B-Catenin, FOXQ1, NFkB, and JAK/STAT pathways as the major drivers of castration-resistant luminal populations with high relevance to human PCa. Importantly, we demonstrate the utility of our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), to aid in developing novel combination treatments with ARSI for advanced PCa patients.
Keyphrases
- single cell
- prostate cancer
- rna seq
- induced apoptosis
- cell cycle arrest
- high throughput
- gene expression
- end stage renal disease
- cell proliferation
- radical prostatectomy
- benign prostatic hyperplasia
- chronic kidney disease
- stem cells
- endoplasmic reticulum stress
- endothelial cells
- oxidative stress
- cell death
- ejection fraction
- machine learning
- pi k akt
- transcription factor
- free survival
- case control