BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance
Mouse tumor organoids are characterized as a model to study 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 targ...
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| Veröffentlicht in: | Nature methods 2018-02, Vol.15 (2), p.134-140 |
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| creator | 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 |
| description | Mouse tumor organoids are characterized as a model to study 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. |
| doi_str_mv | 10.1038/nmeth.4535 |
| format | Article |
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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.</description><identifier>ISSN: 1548-7091</identifier><identifier>EISSN: 1548-7105</identifier><identifier>DOI: 10.1038/nmeth.4535</identifier><identifier>PMID: 29256493</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13 ; 13/106 ; 38/23 ; 631/1647/1407/652 ; 631/1647/334/1874/345 ; 631/67/70 ; 64 ; 64/60 ; 692/308/2778 ; Adenosine diphosphate ; Animal models ; Animals ; Antineoplastic Agents - pharmacology ; ATP Binding Cassette Transporter, Subfamily B - physiology ; Bioinformatics ; Biological Microscopy ; Biological Techniques ; Biomedical Engineering/Biotechnology ; BRCA mutations ; BRCA1 Protein ; BRCA2 protein ; BRCA2 Protein - deficiency ; Breast cancer ; Cancer ; Cell Proliferation - drug effects ; Development and progression ; Drug resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Female ; Genetic aspects ; Genetic engineering ; Genetic modification ; Health aspects ; Homologous recombination ; Homology ; Life Sciences ; 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 ; Proteomics ; Ribose ; Three dimensional models ; Tumor suppressor genes ; Tumor Suppressor Proteins - deficiency ; Tumors</subject><ispartof>Nature methods, 2018-02, Vol.15 (2), p.134-140</ispartof><rights>Springer Nature America, Inc. 2017</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-2df3df4b2d8bc2854f40726fea20e9cf9f2190127a41e07bf67a172268a456023</citedby><cites>FETCH-LOGICAL-c418t-2df3df4b2d8bc2854f40726fea20e9cf9f2190127a41e07bf67a172268a456023</cites><orcidid>0000-0002-5467-7151 ; 0000-0003-2044-9844</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nmeth.4535$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nmeth.4535$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29256493$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duarte, Alexandra A</creatorcontrib><creatorcontrib>Gogola, Ewa</creatorcontrib><creatorcontrib>Sachs, Norman</creatorcontrib><creatorcontrib>Barazas, Marco</creatorcontrib><creatorcontrib>Annunziato, Stefano</creatorcontrib><creatorcontrib>R de Ruiter, Julian</creatorcontrib><creatorcontrib>Velds, Arno</creatorcontrib><creatorcontrib>Blatter, Sohvi</creatorcontrib><creatorcontrib>Houthuijzen, Julia M</creatorcontrib><creatorcontrib>van de Ven, Marieke</creatorcontrib><creatorcontrib>Clevers, Hans</creatorcontrib><creatorcontrib>Borst, Piet</creatorcontrib><creatorcontrib>Jonkers, Jos</creatorcontrib><creatorcontrib>Rottenberg, Sven</creatorcontrib><title>BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance</title><title>Nature methods</title><addtitle>Nat Methods</addtitle><addtitle>Nat Methods</addtitle><description>Mouse tumor organoids are characterized as a model to study 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.</description><subject>13</subject><subject>13/106</subject><subject>38/23</subject><subject>631/1647/1407/652</subject><subject>631/1647/334/1874/345</subject><subject>631/67/70</subject><subject>64</subject><subject>64/60</subject><subject>692/308/2778</subject><subject>Adenosine diphosphate</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>ATP Binding Cassette Transporter, Subfamily B - physiology</subject><subject>Bioinformatics</subject><subject>Biological Microscopy</subject><subject>Biological Techniques</subject><subject>Biomedical Engineering/Biotechnology</subject><subject>BRCA mutations</subject><subject>BRCA1 Protein</subject><subject>BRCA2 protein</subject><subject>BRCA2 Protein - deficiency</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell Proliferation - drug effects</subject><subject>Development and progression</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genetic engineering</subject><subject>Genetic modification</subject><subject>Health aspects</subject><subject>Homologous recombination</subject><subject>Homology</subject><subject>Life Sciences</subject><subject>Mammary gland</subject><subject>Mammary Neoplasms, Animal - drug therapy</subject><subject>Mammary Neoplasms, Animal - metabolism</subject><subject>Mammary Neoplasms, Animal - pathology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Organ Culture Techniques</subject><subject>Organoids</subject><subject>Organoids - drug effects</subject><subject>Organoids - metabolism</subject><subject>Organoids - 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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
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| ispartof | Nature methods, 2018-02, Vol.15 (2), p.134-140 |
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| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online |
| subjects | 13 13/106 38/23 631/1647/1407/652 631/1647/334/1874/345 631/67/70 64 64/60 692/308/2778 Adenosine diphosphate Animal models Animals Antineoplastic Agents - pharmacology ATP Binding Cassette Transporter, Subfamily B - physiology Bioinformatics Biological Microscopy Biological Techniques Biomedical Engineering/Biotechnology BRCA mutations BRCA1 Protein BRCA2 protein BRCA2 Protein - deficiency Breast cancer Cancer Cell Proliferation - drug effects Development and progression Drug resistance Drug Resistance, Neoplasm Drug therapy Female Genetic aspects Genetic engineering Genetic modification Health aspects Homologous recombination Homology Life Sciences 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 Proteomics 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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