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- Title
Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset.
- Authors
Xu, Yi; Nipper, Michael H.; Dominguez, Angel A.; Ye, Zhenqing; Akanuma, Naoki; Lopez, Kevin; Deng, Janice J.; Arenas, Destiny; Sanchez, Ava; Sharkey, Francis E.; Court, Colin M.; Singhi, Aatur D.; Wang, Huamin; Fernandez-Zapico, Martin E.; Sun, Lu-Zhe; Zheng, Siyuan; Chen, Yidong; Liu, Jun; Wang, Pei
- Abstract
Animal studies have demonstrated the ability of pancreatic acinar cells to transform into pancreatic ductal adenocarcinoma (PDAC). However, the tumorigenic potential of human pancreatic acinar cells remains under debate. To address this gap in knowledge, we expand sorted human acinar cells as 3D organoids and genetically modify them through introduction of common PDAC mutations. The acinar organoids undergo dramatic transcriptional alterations but maintain a recognizable DNA methylation signature. The transcriptomes of acinar organoids are similar to those of disease-specific cell populations. Oncogenic KRAS alone do not transform acinar organoids. However, acinar organoids can form PDAC in vivo after acquiring the four most common driver mutations of this disease. Similarly, sorted ductal cells carrying these genetic mutations can also form PDAC, thus experimentally proving that PDACs can originate from both human acinar and ductal cells. RNA-seq analysis reveal the transcriptional shift from normal acinar cells towards PDACs with enhanced proliferation, metabolic rewiring, down-regulation of MHC molecules, and alterations in the coagulation and complement cascade. By comparing PDAC-like cells with normal pancreas and PDAC samples, we identify a group of genes with elevated expression during early transformation which represent potential early diagnostic biomarkers. The cellular origin of human pancreatic ductal adenocarcinoma (PDAC) is still unclear. Here the authors used human primary acinar and ductal cells to successfully reconstitute PDAC tumorigenesis from both lineages and revealed transcriptional changes during early PDAC progression.
- Subjects
PANCREATIC acinar cells; PANCREATIC duct; TRANSCRIPTOMES; COMPLEMENT activation; HUMAN origins; COAGULATION
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-45097-2