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
Department of Cell Systems & Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Nat Commun. 2024 Jan 27;15(1):818. doi: 10.1038/s41467-024-45097-2.
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.
动物研究已经证明胰腺腺泡细胞具有转化为胰腺导管腺癌（PDAC）的能力。然而，人类胰腺腺泡细胞的致瘤潜力仍存在争议。为了填补这一知识空白，我们将分选的人类腺泡细胞扩展为三维类器官，并通过引入常见的PDAC突变对其进行基因改造。腺泡类器官经历了显著的转录改变，但保持了可识别的DNA甲基化特征。腺泡类器官的转录组与疾病特异性细胞群体的转录组相似。单独的致癌性KRAS不会使腺泡类器官发生转化。然而，腺泡类器官在获得该疾病的四种最常见驱动突变后可在体内形成PDAC。同样，携带这些基因突变的分选导管细胞也可形成PDAC，从而通过实验证明PDAC可起源于人类腺泡细胞和导管细胞。RNA测序分析揭示了从正常腺泡细胞向PDAC的转录转变，伴随着增殖增强、代谢重塑、MHC分子下调以及凝血和补体级联反应的改变。通过将类PDAC细胞与正常胰腺和PDAC样本进行比较，我们鉴定出一组在早期转化过程中表达升高的基因，它们代表了潜在的早期诊断生物标志物。
