Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses
de Witte, Chris Jenske; Espejo Valle-Inclan, Jose; Hami, Nizar; Lõhmussaar, Kadi; Kopper, Oded; Vreuls, Celien Philomena Henrieke; Jonges, Geertruida Nellie; van Diest, Paul; Nguyen, Luan; Clevers, Hans; Kloosterman, Wigard Pieter; Cuppen, Edwin; Snippert, Hugo Johannes Gerhardus; Zweemer, Ronald Peter; Witteveen, Petronella Oda; Stelloo, Ellen
(2020) Cell Reports, volume 31, issue 11
(Article)
Abstract
There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories.
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OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity. De Witte et al. employ patient-derived organoids (PDOs) for ex vivo drug screening. Ovarian cancer (OC) PDOs often recapitulate patient drug response to first-line chemotherapy. In addition, OC PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partly explained by genetic aberrations.
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Keywords: chemotherapy, clinical response, drug screening, heterogeneity, organoids, ovarian cancer, WGS, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: We thank members of the Kloosterman and Cuppen laboratories for helpful discussions, Anne Snelting of the Utrecht Platform for Organoid Technology (U-PORT; UMC Utrecht) for patient inclusion and tissue acquisition, Maaike Vreeswijk and Lise van Wijk (Leiden University Medical Center) for providing OC tissues for PDO culturing, Vera Deneer for input regarding clinical pharmacokinetics, the Utrecht Sequencing Facility and Hartwig Medical Foundation for providing sequencing service and data, Hans Bos for acquiring funding, and the Dutch Cancer Registration (IKNL) for providing survival data. The graphical abstract was created with BioRender. This work was supported by the Gieskes Strijbis Foundation (1816199) and the Dutch Cancer Society (UU2015-7743 and RUG-2017-11352). Conceptualization, C.J.d.W. J.E.V.-I. R.P.Z. P.O.W. and E.S.; Methodology, C.J.d.W. J.E.V.-I. O.K. H.C. W.P.K. and E.S.; Software, J.E.V.-I. and L.N.; Validation, C.J.d.W. N.H. and E.S.; Formal Analysis, C.J.d.W. J.E.V.-I. N.H. C.P.H.V. G.N.J. P.v.D. and E.S.; Investigation, C.J.d.W. N.H. K.L. O.K. and E.S.; Resources, C.J.d.W. J.E.V.-I. K.L. O.K. G.N.J. L.N. R.P.Z. P.O.W. and E.S.; Data Curation, C.J.d.W. J.E.V.-I. and E.S.; Writing ? Original Draft, C.J.d.W. and E.S.; Writing ? Review & Editing, all authors; Visualization, C.J.d.W. J.E.V.-I. and E.S.; Supervision, W.P.K. E.C. H.J.G.S. R.P.Z. P.O.W. and E.S.; Project Administration, C.J.d.W. and E.S.; Funding Acquisition, H.C. W.P.K. R.P.Z. and P.O.W. H.C. is an inventor listed on several patents related to organoid technology. H.C. is the founder of OrganoidZ, which employs organoids for drug development. H.C. is the (unpaid) Chief Scientific Officer of Hubrecht Organoid Technology (HUB), a cofounder of Surrozen, and a scientific advisory board member for Kallyope, Merus, and Decibel. H.C. is a nonexecutive board member of Roche and Genentech and a scientific advisor for Life Sciences Partners. His full disclosure is given at https://www.uu.nl/staff/JCClevers/. Funding Information: We thank members of the Kloosterman and Cuppen laboratories for helpful discussions, Anne Snelting of the Utrecht Platform for Organoid Technology (U-PORT; UMC Utrecht) for patient inclusion and tissue acquisition, Maaike Vreeswijk and Lise van Wijk (Leiden University Medical Center) for providing OC tissues for PDO culturing, Vera Deneer for input regarding clinical pharmacokinetics, the Utrecht Sequencing Facility and Hartwig Medical Foundation for providing sequencing service and data, Hans Bos for acquiring funding, and the Dutch Cancer Registration (IKNL) for providing survival data. The graphical abstract was created with BioRender. This work was supported by the Gieskes Strijbis Foundation ( 1816199 ) and the Dutch Cancer Society ( UU2015-7743 and RUG-2017-11352 ). Publisher Copyright: © 2020 The Author(s)
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