Pancreatic cancer organoids recapitulate disease and allow personalized drug screening
Driehuis, Else; Van Hoeck, Arne; Moore, Kat; Kolders, Sigrid; Francies, Hayley E.; Gulersonmez, M. Can; Stigter, Edwin C.A.; Burgering, Boudewijn; Geurts, Veerle; Gracanin, Ana; Bounova, Gergana; Morsink, Folkert H.; Vries, Robert; Boj, Sylvia; Van Es, Johan; Offerhaus, G. Johan A.; Kranenburg, Onno; Garnett, Mathew J.; Wessels, Lodewyk; Cuppen, Edwin; Brosens, Lodewijk A.A.; Clevers, Hans
(2019) Proceedings of the National Academy of Sciences of the United States of America, volume 116, issue 52, pp. 26580 - 26590
(Article)
Abstract
We report the derivation of 30 patient-derived organoid lines (PDOs) from tumors arising in the pancreas and distal bile duct. PDOs recapitulate tumor histology and contain genetic alterations typical of pancreatic cancer. In vitro testing of a panel of 76 therapeutic agents revealed sensitivities currently not exploited in the clinic,
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and underscores the importance of personalized approaches for effective cancer treatment. The PRMT5 inhibitor EZP015556, shown to target MTAP (a gene commonly lost in pancreatic cancer)-negative tumors, was validated as such, but also appeared to constitute an effective therapy for a subset of MTAP-positive tumors. Taken together, the work presented here provides a platform to identify novel therapeutics to target pancreatic tumor cells using PDOs.
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Keywords: Biobank, Cancer, Organoids, Pancreatic cancer, Personalized medicine, General, Journal Article
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. We thank all the employees of U-PORT UMC Utrecht for patient inclusion and tissue acquisition, Kim Boonekamp for her help with MTAP experiments, Fjodor Yousef Yengej for his help with qPCR experiments, Jens Puschhof and Maarten Geurts for their valuable input on drug screen analysis, and the Genomics of Drug Sensitivity in Cancer screening team. This publication and the underlying study were made possible partly on the basis of the data that the Hartwig Medical Foundation and the Center of Personalized Cancer Treatment made available to the study. This work was funded by the Oncode Institute (partly financed by the Dutch Cancer Society), the gravitation program CancerGenomiCs.nl from the Netherlands Organization for Scientific Research, and a Stand Up to Cancer International Translational Cancer Research Grant, a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research (SU2C-AACR-DT1213) and a ZonMw grant (116.006.103). M.J.G. received funding from the Wellcome Trust (206194) and Cancer Research UK (C44943/ A22536). The research of L.A.A.B. is funded by the Dutch Digestive Foundation (MLDS CDG 14-020). Funding Information: aOncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; bHubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands; cCenter for Molecular Medicine, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands; dDivision of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; eWellcome Sanger Institute, Hinxton CB10 1SA, United Kingdom; fDepartment of Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands; gHubrecht Organoid Technology, Utrecht 3584 CM, The Netherlands; hDepartment of Pathology, University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands; iUtrecht Platform for Organoid Technology, Utrecht Medical Center Utrecht, Utrecht 3584 CM, The Netherlands; jHartwig Medical Foundation, 1098 XH Amsterdam, The Netherlands; kCenter for Personalized Cancer Treatment,University Medical Center Utrecht, Utrecht 3584 CM, The Netherlands; and lPrincess Maxima Center, Utrecht 3584 CS, The Netherlands Publisher Copyright: © 2019 National Academy of Sciences. All rights reserved.
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