Journal
CANCER RESEARCH
Volume 81, Issue 15, Pages 3958-3970Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-21-0427
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Funding
- Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH
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This study identifies edge epithelial cell states with oncogenic transcriptional activity in human organs without oncogenic mutations, with a particular focus on pancreatic ductal adenocarcinoma (PDAC). It also highlights the increase in the fraction of acinar cells with age in the pancreas, as well as the significantly higher presence of AE-like cells in human pancreatitis samples.
Pancreatic ductal adenocarcinoma (PDAC) tumors can originate either from acinar or ductal cells in the adult pancreas. We re-analyze multiple pancreas and PDAC single-cell RNA-seq datasets and find a subset of nonmalignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes upregulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are upregulated in human PDAC tumors, and consistently, their promoters are hypomethylated. High expression of these genes is associated with poor patient survival. The fraction of AE-like cells increases with age in healthy pancreatic tissue, which is not explained by clonal mutations, thus pointing to a nongenetic source of variation. The fraction of AE-like cells is also significantly higher in human pancreatitis samples. Finally, we find edge-like states in lung, liver, prostate, and colon tissues, suggesting that subpopulations of healthy cells across tissues can exist in preneoplastic states. Significance: These findings show edge epithelial cell states with oncogenic transcriptional activity in human organs without oncogenic mutations. In the pancreas, the fraction of acinar cells increases with age.
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