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

Ling Huang, Audrey Holtzinger, Ishaan Jagan, Michael Begora, Ines Lohse, Nicholas Ngai, Cristina Nostro, Rennian Wang, Lakshmi B. Muthuswamy, Howard C. Crawford, Cheryl Arrowsmith, Steve E. Kalloger, Daniel J. Renouf, Ashton A. Connor, Sean Cleary, David F. Schaeffer, Michael Roehrl, Ming Sound Tsao, Steven Gallinger, Gordon KellerSenthil K. Muthuswamy

Research output: Contribution to journalArticle

231 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1364-1371
Number of pages8
JournalNature Medicine
Volume21
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Huang, L., Holtzinger, A., Jagan, I., Begora, M., Lohse, I., Ngai, N., Nostro, C., Wang, R., Muthuswamy, L. B., Crawford, H. C., Arrowsmith, C., Kalloger, S. E., Renouf, D. J., Connor, A. A., Cleary, S., Schaeffer, D. F., Roehrl, M., Tsao, M. S., Gallinger, S., ... Muthuswamy, S. K. (2015). Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nature Medicine, 21(11), 1364-1371. https://doi.org/10.1038/nm.3973