Abstract
The epigenomic abnormality of pancreatic ductal adenocarcinoma (PDAC) has rarely been investigated due to its strong heterogeneity. Here, we used single-cell multiomics sequencing to simultaneously analyze the DNA methylome, chromatin accessibility and transcriptome in individual tumor cells of PDAC patients. We identified normal epithelial cells in the tumor lesion, which have euploid genomes, normal patterns of DNA methylation, and chromatin accessibility. Using all these normal epithelial cells as controls, we determined that DNA demethylation in the cancer genome was strongly enriched in heterochromatin regions but depleted in euchromatin regions. There were stronger negative correlations between RNA expression and promoter DNA methylation in cancer cells compared to those in normal epithelial cells. Through in-depth integrated analyses, a set of novel candidate biomarkers were identified, including ZNF667 and ZNF667-AS1, whose expressions were linked to a better prognosis for PDAC patients by affecting the proliferation of cancer cells. Our work systematically revealed the critical epigenomic features of cancer cells in PDAC patients at the single-cell level.
Highlights
Pancreatic cancer, which is named the king of cancers, is highly lethal with extremely poor prognosis[1,2]
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, and surgical resection is the only chance for the cure; no more than 20% of PDAC patients are eligible for this treatment strategy[3]
Characterizing epigenome of normal epithelial cells in the primary tumor tissue Single-cell multiomics sequencing technology was applied to epithelial cells in multiple regions of primary tumor tissues (Pris) and adjacent normal tissues (Adjs) of 13 PDAC patients
Summary
Pancreatic cancer, which is named the king of cancers, is highly lethal with extremely poor prognosis[1,2]. Single-cell sequencing studies have largely revealed intratumoral heterogeneity by gene expression profiles[11,12,13] These studies demonstrated the characteristics of different types of cells in the tumor microenvironment, offering clues on the molecular changes of epithelial cells during cancer progression. A recent study explored the enhancer network in mouse pancreatic cancer model[14], where they included scATAC-seq data from a PDAC patient to show the difference in the chromatin status between normal and cancer cells. These single-cell epigenetic data from patients were quite limited for comprehensive analysis, especially for identifying the global features of PDAC cells. The epigenetic characteristics of PDAC cells remain largely elusive due to their extremely high intratumoral stromal content[15]
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