Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Cell Stem Cell. 2021 Jun 3;28(6):1090-1104.e6. doi: 10.1016/j.stem.2021.03.022. Epub 2021 Apr 28.
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 in maintaining 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 induces cystic growth more effectively in ductal than acinar organoids, whereas KRAS is more effective in modeling cancer in vivo when expressed in acinar compared with ductal organoids. KRAS, but not GNAS, 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.
外分泌胰腺由导管和腺泡组成，是胰腺炎和胰腺导管腺癌 (PDAC) 的起源部位。由于在培养中维持人类腺泡和导管细胞存在挑战，我们对包括 PDAC 在内的人类胰腺疾病的发生和进展的理解受到限制。在这里，我们报告了诱导人类多能干细胞向胰腺导管和腺泡类器官的分化，这些类器官再现了新生儿外分泌胰腺的特性。PDAC 相关癌基因 GNAS 的表达在导管类器官中比在腺泡类器官中更有效地诱导囊性生长，而 KRAS 在表达于腺泡类器官时比在导管类器官中更有效地模拟体内癌症。KRAS 但不是 GNAS ，在培养中和体内诱导腺泡到导管的化生样变化。我们开发了一种用于模拟外分泌发育和疾病的可更新的导管和腺泡类器官来源，并证明了人类胰腺中癌基因作用的谱系趋向性和可塑性。
