Personalized in vitro models for dysplasia and carcinogenesis in the pancreas have been constrained by insufficient differentiation of human pluripotent stem cells (hPSCs) into the exocrine pancreatic lineage. Here, we differentiate hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. PDLOs are generated from hPSCs inducibly expressing oncogenic GNAS, KRAS, or KRAS with genetic covariance of lost CDKN2A and from induced hPSCs derived from a McCune-Albright patient. Each oncogene causes a specific growth, structural, and molecular phenotype in vitro. While transplanted PDLOs with oncogenic KRAS alone form heterogenous dysplastic lesions or cancer, KRAS with CDKN2A loss develop dedifferentiated pancreatic ductal adenocarcinomas. In contrast, transplanted PDLOs with mutant GNAS lead to intraductal papillary mucinous neoplasia-like structures. Conclusively, PDLOs enable in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background.

用于胰腺发育不良和癌变的个性化体外模型受到人类多能干细胞 (hPSC) 分化不足到外分泌胰腺谱系的限制。在这里，我们将 hPSCs 分化为具有人类胰管形态、转录、蛋白质组学和功能特征的胰管样器官 (PDLO)，并在移植到小鼠后进一步成熟。PDLOs 是从诱导表达致癌 GNAS、KRAS 或 KRAS 的 hPSCs 产生的，具有丢失的 CDKN2A 的遗传协方差，以及来自 McCune-Albright 患者的诱导 hPSCs。每个癌基因在体外导致特定的生长、结构和分子表型. 虽然仅具有致癌性 KRAS 的移植 PDLO 会形成异质性发育异常病变或癌症，但具有 CDKN2A 缺失的 KRAS 会发展为去分化的胰腺导管腺癌。相比之下，具有突变 GNAS 的移植 PDLO 会导致导管内乳头状粘液瘤样结构。总之，PDLO 能够从基因定义的背景中对胰腺可塑性、发育异常和癌症形成进行体外和体内研究。