Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.
Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells.
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DOI：
10.1016/j.stem.2021.03.005
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发表时间：
2021-06-03
期刊：
影响因子：
23.9
通讯作者：
Kleger A
中科院分区：
文献类型：
--
作者：
Breunig M;Merkle J;Wagner M;Melzer MK;Barth TFE;Engleitner T;Krumm J;Wiedenmann S;Cohrs CM;Perkhofer L;Jain G;Krüger J;Hermann PC;Schmid M;Madácsy T;Varga Á;Griger J;Azoitei N;Müller M;Wessely O;Robey PG;Heller S;Dantes Z;Reichert M;Günes C;Bolenz C;Kuhn F;Maléth J;Speier S;Liebau S;Sipos B;Kuster B;Seufferlein T;Rad R;Meier M;Hohwieler M;Kleger A
胰腺发育异常和癌变的个性化体外模型受到人多能干细胞（hPSC）向胰腺外分泌谱系分化不足的限制。在这里，我们将hPSC分化为具有人类胰管的形态学，转录，蛋白质组学和功能特征的胰管样器官（PDLO），在移植到小鼠中后进一步成熟。PDLO由诱导表达致癌GNAS、KRAS或具有丢失的CDKN 2A的遗传协方差的KRAS的hPSC以及由源自McCune-Albright患者的诱导hPSC产生。每个癌基因在体外引起特定的生长、结构和分子表型。虽然单独具有致癌KRAS的移植PDLO形成异质性发育不良病变或癌症，但具有CDKN 2A缺失的KRAS发展去分化胰腺导管腺癌。相反，移植的PDLO与突变GNAS导致导管内乳头状粘液瘤样结构。总之，PDLO能够在体外和体内研究胰腺的可塑性，发育不良，和癌症的形成从遗传定义的背景。
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.
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影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
64.5
作者：
Enge M;Arda HE;Mignardi M;Beausang J;Bottino R;Kim SK;Quake SR
通讯作者：
Quake SR
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
9.3
作者：
Baron M;Veres A;Wolock SL;Faust AL;Gaujoux R;Vetere A;Ryu JH;Wagner BK;Shen-Orr SS;Klein AM;Melton DA;Yanai I
通讯作者：
Yanai I
影响因子：
50.3
作者：
Ansieau, Stephane;Bastid, Jeremy;Puisieux, Alain
通讯作者：
Puisieux, Alain