BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance
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...
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| Vydané v: | Nature methods Ročník 15; číslo 2; s. 134 |
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| Hlavní autori: | , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
Nature Publishing Group
01.02.2018
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| ISSN: | 1548-7091, 1548-7105, 1548-7105 |
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| 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 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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| AbstractList | 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 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. 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 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.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 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. |
| Author | Annunziato, Stefano Blatter, Sohvi Clevers, Hans Rottenberg, Sven Gogola, Ewa Duarte, Alexandra A Sachs, Norman R de Ruiter, Julian Velds, Arno Jonkers, Jos Barazas, Marco Borst, Piet Houthuijzen, Julia M van de Ven, Marieke |
| Author_xml | – sequence: 1 givenname: Alexandra A surname: Duarte fullname: Duarte, Alexandra A organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 2 givenname: Ewa surname: Gogola fullname: Gogola, Ewa organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 3 givenname: Norman orcidid: 0000-0002-5467-7151 surname: Sachs fullname: Sachs, Norman organization: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands – sequence: 4 givenname: Marco surname: Barazas fullname: Barazas, Marco organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 5 givenname: Stefano surname: Annunziato fullname: Annunziato, Stefano organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 6 givenname: Julian surname: R de Ruiter fullname: R de Ruiter, Julian organization: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 7 givenname: Arno surname: Velds fullname: Velds, Arno organization: Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 8 givenname: Sohvi surname: Blatter fullname: Blatter, Sohvi organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland – sequence: 9 givenname: Julia M surname: Houthuijzen fullname: Houthuijzen, Julia M organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 10 givenname: Marieke surname: van de Ven fullname: van de Ven, Marieke organization: Mouse Clinic for Cancer and Aging (MCCA), Preclinical Intervention Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 11 givenname: Hans surname: Clevers fullname: Clevers, Hans organization: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Utrecht, The Netherlands – sequence: 12 givenname: Piet surname: Borst fullname: Borst, Piet organization: Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands – sequence: 13 givenname: Jos surname: Jonkers fullname: Jonkers, Jos organization: Division of Molecular Pathology and Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 14 givenname: Sven orcidid: 0000-0003-2044-9844 surname: Rottenberg fullname: Rottenberg, Sven organization: Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland |
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| SubjectTerms | Adenosine diphosphate Animal models Animals Antineoplastic Agents - pharmacology ATP Binding Cassette Transporter, Subfamily B - physiology BRCA1 Protein BRCA2 protein BRCA2 Protein - deficiency Breast cancer Cancer Cell Proliferation - drug effects Drug resistance Drug Resistance, Neoplasm Female Genetic engineering Genetic modification Homologous recombination Homology Mammary gland Mammary Neoplasms, Animal - drug therapy Mammary Neoplasms, Animal - metabolism Mammary Neoplasms, Animal - pathology Mice Mice, Knockout Organ Culture Techniques Organoids Organoids - drug effects Organoids - metabolism Organoids - pathology Poly(ADP-ribose) Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Ribose Three dimensional models Tumor suppressor genes Tumor Suppressor Proteins - deficiency Tumors |
| Title | BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance |
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