期刊
NATURE MEDICINE
卷 21, 期 11, 页码 1364-1371出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3973
关键词
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资金
- Ontario Institute for Cancer Research (OICR) PanCuRx program
- Canadian Cancer Society
- Lee K Margaret Lau Chair for Breast Cancer Research
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant) [115766]
- Janssen
- Merck and Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation (FAPESP)
- Takeda
- Wellcome Trust
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Campbell Family Institute for Breast cancer research
There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and fat drug screening to identify precision therapy strategies.
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