Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice.
Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice.
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DOI：
10.1084/jem.20191257
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发表时间：
2020-06-01
期刊：
影响因子：
--
通讯作者：
Berns A
中科院分区：
文献类型：
--
作者：
Badhai J;Pandey GK;Song JY;Krijgsman O;Bhaskaran R;Chandrasekaran G;Kwon MC;Bombardelli L;Monkhorst K;Grasso C;Zevenhoven J;van der Vliet J;Cozijnsen M;Krimpenfort P;Peeper D;van Lohuizen M;Berns A
Badhai等人。描述一种联合缺失BAP1、NF2和CDKN2ab的间皮瘤小鼠模型，该模型显示了快速发病并概括了人类间皮瘤，包括其对标准治疗的反应。这种本土模型非常适合测试癌症免疫疗法。我们已经建立了恶性间皮瘤(MM)的小鼠模型，其基础是BAP1、NF2和CDKN2ab肿瘤抑制基因在各种组合中的破坏，就像在人类MM中经常观察到的那样。胸腔间皮衬里所有这三个基因位点的失活导致了高度侵袭性的MM，概括了在人类患者中观察到的组织学特征和基因表达谱。肿瘤也表现出类似的炎症表型。BAP1缺失本身并不会导致多发性骨髓瘤，但当与Nf2和CDKN2ab(以下简称BNC)结合使用时，会显著加速多发性骨髓瘤的发展。肿瘤的加速发展伴随着多梳抑制的增加和EZH2介导的H3K27me3向启动子位置的重新分布，同时伴随着PI3K和MAPK通路的激活。用顺铂和培美曲塞治疗BNC肿瘤小鼠，这是目前的一线治疗方法，延长了存活期。这使得本文描述的自体小鼠模型非常适合于探索MM的发病机制，并验证包括免疫治疗在内的新的MM治疗方案。
Badhai et al. describe a mouse model of mesothelioma with combined deletion of Bap1, Nf2, and Cdkn2ab that shows rapid onset and recapitulates human mesothelioma including its response to the standard treatment. This autochthonous model is well suited for testing cancer immunotherapies. We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype. Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption. The accelerated tumor development is accompanied by increased Polycomb repression and EZH2-mediated redistribution of H3K27me3 toward promoter sites with concomitant activation of PI3K and MAPK pathways. Treatment of BNC tumor–bearing mice with cisplatin and pemetrexed, the current frontline treatment, prolongs survival. This makes the autochthonous mouse model described here very well suited to explore the pathogenesis of MM and validate new treatment regimens for MM, including immunotherapy.
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影响因子：
50.3
作者：
Jongsma, Johan;van Montfort, Erwin;Berns, Anton
通讯作者：
Berns, Anton
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11.2
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12.3
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影响因子：
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影响因子：
28.2
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通讯作者：
Ladanyi M