Epigenetic loss of heterogeneity from low to high grade localized prostate tumours.
Nat Commun, 2021/12/15;12(1):7292.
Eksi SE[1, 2], Chitsazan A[3], Sayar Z[3, 4], Thomas GV[3, 5], Fields AJ[6], Kopp RP[7], Spellman PT[3, 6], Adey AC[8, 9]
Affiliations
PMID: 34911933DOI: 10.1038/s41467-021-27615-8
Impact factor: 17.694
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.
MeSH terms
CDX2 Transcription Factor; Calcium-Binding Proteins; Cell Adhesion Molecules, Neuronal; Cohort Studies; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Hepatocyte Nuclear Factor 3-alpha; Homeodomain Proteins; Humans; Loss of Heterozygosity; Male; Neoplasm Staging; Neural Cell Adhesion Molecules; Prostatic Neoplasms
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