BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance
Duarte, Alexandra A.; Gogola, Ewa; Sachs, Norman; Barazas, Marco; Annunziato, Stefano; R De Ruiter, Julian; Velds, Arno; Blatter, Sohvi; Houthuijzen, Julia M.; Van De Ven, Marieke; Clevers, Hans; Borst, Piet; Jonkers, Jos; Rottenberg, Sven
(2018) Nature Methods, volume 15, issue 2, pp. 134 - 140
(Article)
Abstract
Poly(ADP-ribose) polymerase inhibition (PARPi) is a promising new therapeutic approach for the treatment of cancers that show homologous recombination deficiency (HRD). Despite the success of PARPi in targeting HRD in tumors that lack the tumor suppressor function of BRCA1 or BRCA2, drug resistance poses a major obstacle. We developed three-dimensional
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cancer organoids derived from genetically engineered mouse models (GEMMs) for BRCA1- and BRCA2-deficient cancers. Unlike conventional cell lines or mammospheres, organoid cultures can be efficiently derived and rapidly expanded in vitro. Orthotopically transplanted organoids give rise to mammary tumors that recapitulate the epithelial morphology and preserve the drug response of the original tumor. Notably, GEMM-tumor-derived organoids can be easily genetically modified, making them a powerful tool for genetic studies of tumor biology and drug resistance.
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Keywords: Biotechnology, Biochemistry, Molecular Biology, Cell Biology
ISSN: 1548-7091
Publisher: Nature Publishing Group
Note: Funding Information: We wish to thank the members of the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Ageing (MCCA) at the Netherlands Cancer Institute (NKI) N. Domanitskaia, N. Gerhards, G. Lakner, O. Levionnois, N. Regenscheit and M. Siffert (Vetsuisse Bern) for their technical support with the animal experiments. We are grateful to B. Evers (NKI) for providing the iKRUNC-Puro vector, H. van der Gulden (NKI) for her assistance with the genotyping procedure, and the NKI animal facility, animal pathology facility, flow cytometry facility and genomics core facility for their excellent service. Financial support came from the Dutch Cancer Society (KWF 2011-5220 and 2014-6532 to S.R. and J.J.), the Netherlands Organization for Scientific Research (VICI 91814643, Cancer Genomics Netherlands and a National Roadmap grant for Large-Scale Research Facilities to J.J., VENI 916.15.182 to N.S.), the Netherlands Genomics Initiative Zenith (93512009 to J.J.), the Swiss National Science Foundation (310030_156869 to S.R.), the Swiss Cancer Research Foundation (MD-PhD-3446-01-2014 to S.B.) and the European Union (ERC CoG-681572 to S.R. and ERC synergy grant 319661 COMBATCANCER to J.J.). Publisher Copyright: © 2018 Nature America, Inc. Part of Springer Nature. All rights reserved. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.
(Peer reviewed)