@article{47117f9b8c7b4ed0853abc7ce62ea938,
title = "Epigenetic loss of heterogeneity from low to high grade localized prostate tumours",
abstract = "Identifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Despite this loss, high-grade tumours exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory programme. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumours. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumours, critical for molecular stratification of the disease.",
author = "Eksi, {Sebnem Ece} and Alex Chitsazan and Zeynep Sayar and Thomas, {George V.} and Fields, {Andrew J.} and Kopp, {Ryan P.} and Spellman, {Paul T.} and Adey, {Andrew C.}",
note = "Funding Information: We are grateful to all patients who participated to the OHSU study (IRB #18321) that provided tissue from prostatectomy whole-mounts. R.P.K. was funded by the Collins Medical Trust for this study. We are also grateful to the Biolibrary and the Histopathology Shared Resource (HSR) at OHSU for providing patient samples, specifically Aletha Letsch and Cheyenne Martin. The Biolibrary and HSR was supported by NIH grants P30 CA069533 and P30 CA069533 13S5 through the Knight Cancer Institute. We thank Erin Watson for collecting patient information. We thank the Spellman lab and the prostate cancer working group in CEDAR for engaging discussions. We are grateful for the collaborative environment in the Knight Cancer Institute and productive interactions with the Grey, the Chang and the Adey labs. We thank Kemal Sonmez for his input on single-cell data analysis. We thank Crystal Shaw from the Advanced Light Microscopy Core and Dorian LaTocha from the Flow Cytometry Core at OHSU for their technical help. We thank Shelley Barton, Hisham Mohammed, Joshua Saldivar, Stefanie Linch and Lindsey Minter for providing feedback on the manuscript. This project was supported by funding (CEDAR3410918) from the Cancer Early Detection Advanced Research Centre at Oregon health & Science University, Knight Cancer Institute (S.E.E.). Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = dec,
doi = "10.1038/s41467-021-27615-8",
language = "English (US)",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}