Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer
Potent Antitumor Activity of Liposomal Irinotecan in an Organoid- and CRISPR-Cas9-Based Murine Model of Gallbladder Cancer
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DOI：
10.3390/cancers11121904
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发表时间：
2019-12-01
期刊：
影响因子：
5.2
通讯作者：
Saborowski, Michael
中科院分区：
文献类型：
--
作者：
Erlangga, Zulrahman;Wolff, Katharina;Saborowski, Michael
胆囊癌与预后不良有关，准确的体内模型将是提高我们对这种致命疾病的理解和开发更好治疗方案的基础。我们已经建立了一种基于移植的胆囊癌小鼠模型，该模型在组织学上模拟了人类疾病，包括远处转移的发展。通过逆转录病毒转导或用CRISPR/Cas9编码质粒转染来遗传修饰小鼠胆囊衍生的类器官，从而允许快速产生复杂的癌症基因型。我们在两个最常见的致癌驱动Kras和ERBB 2的存在下表征模型，并提供证据表明肿瘤组织学高度依赖于驱动癌基因。此外，我们通过显示脂质体伊立替康（Nal-IRI）保留在肿瘤细胞中并与常规伊立替康相比显著延长胆囊癌荷瘤小鼠的生存期，证明了该模型用于新型治疗方法的临床前评估的实用性。
Gallbladder cancer is associated with a dismal prognosis, and accurate in vivo models will be elemental to improve our understanding of this deadly disease and develop better treatment options. We have generated a transplantation-based murine model for gallbladder cancer that histologically mimics the human disease, including the development of distant metastasis. Murine gallbladder-derived organoids are genetically modified by either retroviral transduction or transfection with CRISPR/Cas9 encoding plasmids, thereby allowing the rapid generation of complex cancer genotypes. We characterize the model in the presence of two of the most frequent oncogenic drivers-Kras and ERBB2-and provide evidence that the tumor histology is highly dependent on the driver oncogene. Further, we demonstrate the utility of the model for the preclinical assessment of novel therapeutic approaches by showing that liposomal Irinotecan (Nal-IRI) is retained in tumor cells and significantly prolongs the survival of gallbladder cancer-bearing mice compared to conventional irinotecan.