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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Bibliographic Details
Published in:Nature methods Vol. 15; no. 2; p. 134
Main Authors: 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
Format: Journal Article
Language:English
Published: United States Nature Publishing Group 01.02.2018
Subjects:
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
ISSN:1548-7091, 1548-7105, 1548-7105
Online Access:Get full text
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Summary: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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ISSN:1548-7091
1548-7105
1548-7105
DOI:10.1038/nmeth.4535