Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids

被引：78

作者：

Huang, Ling ^{[1
,2
]}

Desai, Ridhdhi ^{[1
,2
]}

Conrad, Daniel N. ^{[3
]}

Leite, Nayara C. ^{[4
]}

Akshinthala, Dipikaa ^{[1
,2
]}

Lim, Christine Maria ^{[1
,2
]}

Gonzalez, Raul ^{[1
,5
]}

Muthuswamy, Lakshmi B. ^{[1
,2
]}

Gartner, Zev ^{[3
,6
,7
]}

Muthuswamy, Senthil K. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA

[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA

[3] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA

[4] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[6] Chan Zuckerberg Biohub, San Francisco, CA 94158 USA

[7] NSF Ctr Cellular Construct, San Francisco, CA 94158 USA

来源：

CELL STEM CELL | 2021年 / 28卷 / 06期

关键词：

INTRAEPITHELIAL NEOPLASIA; EXPRESSION; CANCER; PROGRESSION; ENDOCRINE; KRAS; DIFFERENTIATION; ADENOCARCINOMA; REGENERATION; GENERATION;

D O I：

10.1016/j.stem.2021.03.022

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

The exocrine pancreas, consisting of ducts and acini, is the site of origin of pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Our understanding of the genesis and progression of human pancreatic diseases, including PDAC, is limited because of challenges inmaintaining human acinar and ductal cells in culture. Here we report induction of human pluripotent stem cells toward pancreatic ductal and acinar organoids that recapitulate properties of the neonatal exocrine pancreas. Expression of the PDAC-associated oncogene GNAS(R201C) induces cystic growth more effectively in ductal than acinar organoids, whereas KRAS(G12D) is more effective in modeling cancer in vivo when expressed in acinar compared with ductal organoids. KRAS(G12D), but not GNAS(R201C), induces acinar-to-ductal metaplasia-like changes in culture and in vivo. We develop a renewable source of ductal and acinar organoids for modeling exocrine development and diseases and demonstrate lineage tropism and plasticity for oncogene action in the human pancreas.

引用

页码：1090 / +

页数：21