Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells

Kirk, J. S.; Wang, J.; Tracz, A.; Long, M.; Rosario, S. R.; Ji, Y.; Kumar, R.; Liu, X.; Singh, P. K.; Puzanov, I.; Chatta, G.; Cheng, Q.; Huang, J.; Wrana, J. L.; Lovell, J.; Yu, H.; Liu, S.; Shen, M. M.; Liu, T.; Tang, D. G.

doi:10.1101/2023.03.03.530998

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bioRxiv · 10.1101/2023.03.03.530998

Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells

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Abstract

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/{beta}-Catenin, FOXQ1, NF{kappa}B, 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. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/530998v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@8bd384org.highwire.dtl.DTLVardef@1ebc004org.highwire.dtl.DTLVardef@8b4dbforg.highwire.dtl.DTLVardef@19d7052_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Kirk, J. S., Wang, J., Tracz, A., Long, M., Rosario, S. R., Ji, Y., Kumar, R., Liu, X., Singh, P. K., Puzanov, I., Chatta, G., Cheng, Q., Huang, J., Wrana, J. L., Lovell, J., Yu, H., Liu, S., Shen, M. M., Liu, T., Tang, D. G.. 2023-03-06. Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells. https://doi.org/10.1101/2023.03.03.530998

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