A Transcriptionally Distinct Subpopulation of Healthy Acinar Cells Exhibit Features of Pancreatic Progenitors and PDAC.

Autor:	Gopalan V; Cancer Data Science Laboratory, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. vishaka.gopalan@nih.gov sridhar.hannenhalli@nih.gov., Singh A; Cancer Data Science Laboratory, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland., Rashidi Mehrabadi F; Cancer Data Science Laboratory, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.; Department of Computer Science, Indiana University, Bloomington, Indiana., Wang L; Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Ruppin E; Cancer Data Science Laboratory, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland., Arda HE; Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland., Hannenhalli S; Cancer Data Science Laboratory, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland. vishaka.gopalan@nih.gov sridhar.hannenhalli@nih.gov.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Aug 01; Vol. 81 (15), pp. 3958-3970. Date of Electronic Publication: 2021 May 28.
DOI:	10.1158/0008-5472.CAN-21-0427
Abstrakt:	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 pre-neoplastic 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. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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