Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology.
Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology.
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DOI：
10.1093/neuonc/noad097
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发表时间：
2023-11-02
期刊：
影响因子：
15.9
通讯作者：
中科院分区：
文献类型：
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恶性周围神经鞘瘤(MPNST)是一种侵袭性软组织肉瘤，常发生于1型神经纤维瘤病(NF1)患者。为了解决MPNST对新疗法的迫切需求，我们的目标是建立一个体外3D平台，准确地捕捉MPNST的基因组多样性，并以中等吞吐量的方式利用患者来源的异种移植(PDX)进行体内药物筛选研究。对所有的PDX-肿瘤对进行基因组分析。选择PDX用于组装成3D显微组织。基于我们实验室以前的工作，我们评估了药物(曲贝替丁、奥拉帕利布和米达美替尼)的体外和体内。对于3D显微组织研究，蔡司Axio观察者评估的终点是细胞存活率。在PDX药物研究中，肿瘤体积每周测量两次。进行批量RNA测序，以确定细胞中的富含途径。我们开发了13个与NF1相关的MPNST-PDX，并发现了NF1(100%)、SUZ12(85%)、EED(15%)、TP53(15%)、CDKN2A(85%)和8号染色体(77%)的突变或结构异常。我们成功地将PDX组装成3D显微组织，分为健壮(48小时存活率90%)、良好(50%)或不可用(50%)三类。我们评估了药物对“健壮的”或“良好的”微组织的反应，即MN-2、JH-2-002、JH-2-079-c和Wu-225。体外药物反应预测体内药物反应，并在选定的模型中观察到增强的药物效应。这些数据支持了在代表人类状况的系统中成功地建立用于药物发现和MPNST生物探索的新型3D平台。
Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas that often develop in patients with neurofibromatosis type 1 (NF1). To address the critical need for novel therapeutics in MPNST, we aimed to establish an ex vivo 3D platform that accurately captured the genomic diversity of MPNST and could be utilized in a medium-throughput manner for drug screening studies to be validated in vivo using patient-derived xenografts (PDX). Genomic analysis was performed on all PDX-tumor pairs. Selected PDX were harvested for assembly into 3D microtissues. Based on prior work in our labs, we evaluated drugs (trabectedin, olaparib, and mirdametinib) ex vivo and in vivo. For 3D microtissue studies, cell viability was the endpoint as assessed by Zeiss Axio Observer. For PDX drug studies, tumor volume was measured twice weekly. Bulk RNA sequencing was performed to identify pathways enriched in cells. We developed 13 NF1-associated MPNST-PDX and identified mutations or structural abnormalities in NF1 (100%), SUZ12 (85%), EED (15%), TP53 (15%), CDKN2A (85%), and chromosome 8 gain (77%). We successfully assembled PDX into 3D microtissues, categorized as robust (>90% viability at 48 h), good (>50%), or unusable (<50%). We evaluated drug response to “robust” or “good” microtissues, namely MN-2, JH-2-002, JH-2-079-c, and WU-225. Drug response ex vivo predicted drug response in vivo, and enhanced drug effects were observed in select models. These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
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影响因子：
9.8
作者：
Allaway, Robert J.;La Rosa, Salvatore;Gosline, Sara J. C.
通讯作者：
Gosline, Sara J. C.
影响因子：
3.2
作者：
Brancato, Virginia;Kundu, Banani;Kundu, Subhas C.
通讯作者：
Kundu, Subhas C.
DOI：
10.1039/c8ib00111a
发表时间：
2018-09-17
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
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作者：
Crampton AL;Cummins KA;Wood DK
通讯作者：
Wood DK
影响因子：
8.8
作者：
Li S;Shen D;Shao J;Crowder R;Liu W;Prat A;He X;Liu S;Hoog J;Lu C;Ding L;Griffith OL;Miller C;Larson D;Fulton RS;Harrison M;Mooney T;McMichael JF;Luo J;Tao Y;Goncalves R;Schlosberg C;Hiken JF;Saied L;Sanchez C;Giuntoli T;Bumb C;Cooper C;Kitchens RT;Lin A;Phommaly C;Davies SR;Zhang J;Kavuri MS;McEachern D;Dong YY;Ma C;Pluard T;Naughton M;Bose R;Suresh R;McDowell R;Michel L;Aft R;Gillanders W;DeSchryver K;Wilson RK;Wang S;Mills GB;Gonzalez-Angulo A;Edwards JR;Maher C;Perou CM;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ
影响因子：
28.2
作者：
通讯作者：
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