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

Authors

Ling Huang, Ontario Cancer Institute University of Toronto
Audrey Holtzinger, Ontario Cancer Institute University of Toronto
Ishaan Jagan, Ontario Cancer Institute University of Toronto
Michael Begora, Ontario Cancer Institute University of Toronto
Ines Lohse, Ontario Cancer Institute University of Toronto
Nicholas Ngai, Ontario Cancer Institute University of Toronto
Cristina Nostro, Ontario Cancer Institute University of Toronto
Rennian Wang, Western UniversityFollow
Lakshmi B. Muthuswamy, Ontario Cancer Institute University of Toronto
Howard C. Crawford, University of Michigan, Ann Arbor
Cheryl Arrowsmith, Ontario Cancer Institute University of Toronto
Steve E. Kalloger, Vancouver General Hospital
Daniel J. Renouf, The University of British Columbia
Ashton A. Connor, University of Toronto
Sean Cleary, University of Toronto
David F. Schaeffer, Vancouver General Hospital
Michael Roehrl, Ontario Cancer Institute University of Toronto
Ming Sound Tsao, Ontario Cancer Institute University of Toronto
Steven Gallinger, University of Toronto
Gordon Keller, Ontario Cancer Institute University of Toronto
Senthil K. Muthuswamy, Ontario Cancer Institute University of Toronto

Document Type

Article

Publication Date

11-1-2015

Journal

Nature Medicine

Volume

21

Issue

11

First Page

1364

Last Page

1371

URL with Digital Object Identifier

10.1038/nm.3973

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.