BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance
BRCA-deficient mouse mammary tumor organoids to study cancer-drug resistance
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DOI：
10.1038/nmeth.4535
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发表时间：
2018-02-01
期刊：
影响因子：
48
通讯作者：
Rottenberg, Sven
中科院分区：
文献类型：
--
作者：
Duarte, Alexandra A.;Gogola, Ewa;Rottenberg, Sven
聚（ADP-核糖）聚合酶抑制（PARPi）是用于治疗显示同源重组缺陷（HRD）的癌症的有前景的新治疗方法。尽管PARPi在缺乏BRCA 1或BRCA 2的肿瘤抑制功能的肿瘤中靶向HRD方面取得了成功，但耐药性构成了主要障碍。我们开发了来自BRCA 1和BRCA 2缺陷型癌症的基因工程小鼠模型（GEMM）的三维癌症类器官。与传统的细胞系或乳腺球不同，类器官培养物可以在体外有效地衍生和快速扩增。原位移植的类器官引起乳腺肿瘤，其重现上皮形态并保留原始肿瘤的药物反应。值得注意的是，GEM肿瘤衍生的类器官可以很容易地进行遗传修饰，使其成为肿瘤生物学和耐药性遗传研究的有力工具。
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, GEM-tumor-derived organoids can be easily genetically modified, making them a powerful tool for genetic studies of tumor biology and drug resistance.