Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset

Yi Xu, Michael H. Nipper, Angel A. Dominguez, Zhenqing Ye, Naoki Akanuma, Kevin Lopez, Janice J. Deng, Destiny Arenas, Ava Sanchez, Francis E. Sharkey, Colin M. Court, Aatur D. Singhi, Huamin Wang, Martin E. Fernandez-Zapico, Lu-Zhe Sun, Siyuan Zheng, Yidong Chen, Jun Liu () and Pei Wang ()
Additional contact information
Yi Xu: University of Texas Health Science Center at San Antonio
Michael H. Nipper: University of Texas Health Science Center at San Antonio
Angel A. Dominguez: University of Texas Health Science Center at San Antonio
Zhenqing Ye: University of Texas Health Science Center at San Antonio
Naoki Akanuma: University of Texas Health Science Center at San Antonio
Kevin Lopez: University of Texas Health Science Center at San Antonio
Janice J. Deng: University of Texas Health Science Center at San Antonio
Destiny Arenas: University of Texas Health Science Center at San Antonio
Ava Sanchez: University of Texas Health Science Center at San Antonio
Francis E. Sharkey: University of Texas Health Science Center at San Antonio
Colin M. Court: University of Texas Health Science Center at San Antonio
Aatur D. Singhi: University of Pittsburgh Medical Center
Huamin Wang: University of Texas MD Anderson Cancer Center
Martin E. Fernandez-Zapico: Mayo Clinic
Lu-Zhe Sun: University of Texas Health Science Center at San Antonio
Siyuan Zheng: University of Texas Health Science Center at San Antonio
Yidong Chen: University of Texas Health Science Center at San Antonio
Jun Liu: University of Texas Health Science Center at San Antonio
Pei Wang: University of Texas Health Science Center at San Antonio

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45097-2

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