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Nat Med. 2015 Nov;21(11):1364-71. doi: 10.1038/nm.3973. Epub 2015 Oct 26.

Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.

Author information

1
Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
2
McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
3
Department of Physiology, Western University, London, Ontario, Canada.
4
Department of Pharmacology, Western University, London, Ontario, Canada.
5
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
6
Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
7
Structural Genomics Consortium, Toronto, Ontario, Canada.
8
Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
9
Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
10
Pancreas Centre British Columbia, Vancouver, British Columbia, Canada.
11
Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
12
Division of General Surgery, University of Toronto, Toronto, Ontario, Canada.
13
Department of Pathology, University Health Network, Toronto, Ontario, Canada.

Abstract

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 for drug screening to identify precision therapy strategies.

PMID:
26501191
PMCID:
PMC4753163
DOI:
10.1038/nm.3973
[Indexed for MEDLINE]
Free PMC Article
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