Nature Communications: Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset (Chen, Zheng)

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 &
Pei Wang

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 the 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 this disease’s four most common driver mutations. 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 reveals 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.

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