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 Muthuswamy,Howard C. Crawford,Cheryl H. Arrowsmith,Cheryl H. Arrowsmith,Steve E. Kalloger,Daniel J. Renouf,Ashton A. Connor,Sean P. Cleary,David F. Schaeffer,David F. Schaeffer,Michael H.A. Roehrl,Ming-Sound Tsao,Steven Gallinger,Gordon Keller,Senthil K. Muthuswamy +22 more
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TLDR
Pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.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.read more
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Modeling Development and Disease with Organoids
TL;DR: 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina, and hold promise to predict drug response in a personalized fashion.
Journal ArticleDOI
Organoids in cancer research
Jarno Drost,Hans Clevers +1 more
TL;DR: In this Review, Drost and Clevers discuss the recent advances in organoid models of cancer and how they can be exploited to drive the translation of basic cancer research into novel patient-specific treatment regimens in the clinic.
Journal ArticleDOI
Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine
Chantal Pauli,Chantal Pauli,Chantal Pauli,Benjamin D. Hopkins,Davide Prandi,Reid Shaw,Tarcisio Fedrizzi,Andrea Sboner,Andrea Sboner,Verena Sailer,Verena Sailer,Michael A. Augello,Michael A. Augello,Loredana Puca,Rachele Rosati,Terra J. McNary,Yelena Churakova,Cynthia Cheung,Joanna Triscott,David J. Pisapia,David J. Pisapia,Rema Rao,Rema Rao,Juan Miguel Mosquera,Juan Miguel Mosquera,Brian D. Robinson,Brian D. Robinson,Bishoy Faltas,Bishoy Faltas,Brooke E Emerling,Vijayakrishna K. Gadi,Brady Bernard,Olivier Elemento,Olivier Elemento,Himisha Beltran,Himisha Beltran,Francesca Demichelis,Francesca Demichelis,Christopher J. Kemp,Carla Grandori,Lewis C. Cantley,Mark A. Rubin,Mark A. Rubin +42 more
TL;DR: A robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids is described, which promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options where standard clinical options have been exhausted.
Journal ArticleDOI
Disease Modeling in Stem Cell-Derived 3D Organoid Systems
TL;DR: Recent advances in the application of organoids in studying cancer and hereditary diseases, as well as in the examination of host cell-microorganism interactions are discussed.
Journal ArticleDOI
Interrogating open issues in cancer precision medicine with patient-derived xenografts
Annette T. Byrne,D Alferez,Frédéric Amant,Daniela Annibali,Joaquín Arribas,Andrew V. Biankin,Andrew V. Biankin,Alejandra Bruna,Eva Budinská,Carlos Caldas,David K. Chang,Robert Clarke,Hans Clevers,George Coukos,Virginie Dangles-Marie,S. Gail Eckhardt,Eva González-Suárez,Els Hermans,Manuel Hidalgo,Monika A. Jarzabek,Steven de Jong,Jos Jonkers,Kristel Kemper,Luisa Lanfrancone,Gunhild Mari Mælandsmo,Elisabetta Marangoni,Jean-Christophe Marine,Enzo Medico,Jens Henrik Norum,Héctor G. Palmer,Daniel S. Peeper,Pier Giuseppe Pelicci,Alejandro Piris-Giménez,Sergio Roman-Roman,Oscar M. Rueda,Joan Seoane,Violeta Serra,Laura Soucek,Dominique Vanhecke,Alberto Villanueva,Emilie Vinolo,Andrea Bertotti,Livio Trusolino +42 more
TL;DR: Patient derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology as mentioned in this paper, and the ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and the implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions.
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