A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and PDAC

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 non-malignant acinar cells, which we refer to as acinar edge (AE) cells, whose transcriptomes highly diverge from a typical acinar cell in each dataset. Genes up-regulated among AE cells are enriched for transcriptomic signatures of pancreatic progenitors, acinar dedifferentiation, and several oncogenic programs. AE-upregulated genes are up-regulated in human PDAC tumors, and consistently, their promoters are hypo-methylated. 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 non-genetic source of variation. We also find edge-like states in lung and liver tissues, suggesting that sub-populations of healthy cells across tissues can exist in pre-malignant states.