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Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids.
Huang, Ling; Holtzinger, Audrey; Jagan, Ishaan; BeGora, Michael; Lohse, Ines; Ngai, Nicholas; Nostro, Cristina; Wang, Rennian; Muthuswamy, Lakshmi B; Crawford, Howard C; Arrowsmith, Cheryl; Kalloger, Steve E; Renouf, Daniel J; Connor, Ashton A; Cleary, Sean; Schaeffer, David F; Roehrl, Michael; Tsao, Ming-Sound; Gallinger, Steven; Keller, Gordon; Muthuswamy, Senthil K.
Afiliación
  • Huang L; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Holtzinger A; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Jagan I; McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
  • BeGora M; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Lohse I; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Ngai N; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Nostro C; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Wang R; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Muthuswamy LB; McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada.
  • Crawford HC; Department of Physiology, Western University, London, Ontario, Canada.
  • Arrowsmith C; Department of Pharmacology, Western University, London, Ontario, Canada.
  • Kalloger SE; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Renouf DJ; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
  • Connor AA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • Cleary S; Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada.
  • Schaeffer DF; Structural Genomics Consortium, Toronto, Ontario, Canada.
  • Roehrl M; Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.
  • Tsao MS; Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
  • Gallinger S; Pancreas Centre British Columbia, Vancouver, British Columbia, Canada.
  • Keller G; Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada.
  • Muthuswamy SK; Pancreas Centre British Columbia, Vancouver, British Columbia, Canada.
Nat Med ; 21(11): 1364-71, 2015 Nov.
Article en En | MEDLINE | ID: mdl-26501191
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Páncreas / Neoplasias Pancreáticas / Organoides / Carcinoma Ductal Pancreático / Células Madre Pluripotentes / Desoxicitidina / Antimetabolitos Antineoplásicos Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2015 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Páncreas / Neoplasias Pancreáticas / Organoides / Carcinoma Ductal Pancreático / Células Madre Pluripotentes / Desoxicitidina / Antimetabolitos Antineoplásicos Tipo de estudio: Diagnostic_studies / Prognostic_studies / Screening_studies Límite: Animals / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2015 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos