In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example.
In Vivo Expansion of Cancer Stemness Affords Novel Cancer Stem Cell Targets: Malignant Rhabdoid Tumor as an Example.
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DOI：
10.1016/j.stemcr.2018.07.010
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发表时间：
2018-09-11
影响因子：
5.9
通讯作者：
Dekel B
中科院分区：
文献类型：
--
作者：
Golan H;Shukrun R;Caspi R;Vax E;Pode-Shakked N;Goldberg S;Pleniceanu O;Bar-Lev DD;Mark-Danieli M;Pri-Chen S;Jacob-Hirsch J;Kanter I;Trink A;Schiby G;Bilik R;Kalisky T;Harari-Steinberg O;Toren A;Dekel B
癌症干细胞（CSC）鉴定依赖于从新鲜肿瘤样品中分选的细胞亚群的移植测定。在这里，我们试图绕过丰富的肿瘤来源和预定的免疫选择的限制，在体内繁殖患者来源的异种移植物（PDX）从人恶性横纹肌样瘤（MRT），一种罕见的和致命的儿科肿瘤，到一个先进的状态，其中大多数细胞的行为作为CSC。然后，通过比较一系列PDX的转录组学来探测干细胞，所述PDX产生上皮向间充质转化、侵袭/运动性、转移和自我更新的基因签名，从而精确定位推定的MRT CSC标志物。这些推定的CSC分子的相关性通过根据一种这样的分子从早期传代的PDX中分选致瘤性级分、解读存档的原发性肿瘤中的表达并测试CSC分子抑制对MRT生长的影响来分析。使用这个平台，我们确定ALDH 1和赖氨酰氧化酶（LOX）作为相关的目标，并为罕见的儿科癌症的目标和药物发现提供了一个更大的框架。人恶性横纹肌样瘤（MRT）可以作为肿瘤异种移植物在体内增殖长期增殖的PDX富集CSC频率而不需要免疫选择干样MRT异种移植物中的独特基因签名揭示了推定的CSC生物标志物推定的CSC生物标志物的筛选允许鉴定治疗靶标Golan et al.证明人MRT异种移植物的长期繁殖强烈地富集癌症干细胞频率。这又被用于鉴定MRT中的潜在治疗靶点，如赖氨酰氧化酶，并公开了一个平台，以鉴定正在寻找新疗法的其他罕见儿科肿瘤中的CSC靶点。
Cancer stem cell (CSC) identification relies on transplantation assays of cell subpopulations sorted from fresh tumor samples. Here, we attempt to bypass limitations of abundant tumor source and predetermined immune selection by in vivo propagating patient-derived xenografts (PDX) from human malignant rhabdoid tumor (MRT), a rare and lethal pediatric neoplasm, to an advanced state in which most cells behave as CSCs. Stemness is then probed by comparative transcriptomics of serial PDXs generating a gene signature of epithelial to mesenchymal transition, invasion/motility, metastasis, and self-renewal, pinpointing putative MRT CSC markers. The relevance of these putative CSC molecules is analyzed by sorting tumorigenic fractions from early-passaged PDX according to one such molecule, deciphering expression in archived primary tumors, and testing the effects of CSC molecule inhibition on MRT growth. Using this platform, we identify ALDH1 and lysyl oxidase (LOX) as relevant targets and provide a larger framework for target and drug discovery in rare pediatric cancers. Human malignant rhabdoid tumor (MRT) can be propagated in vivo as tumor xenografts Long-term propagated PDX enrich for CSC frequency with no need for immune selection Distinct gene signature in stem-like MRT xenografts reveals putative CSC biomarkers Screening of putative CSC biomarkers allows identification of therapeutic targets Golan et al. demonstrate that long-term propagation of human MRT xenografts robustly enriches for cancer stem cell frequency. This was exploited in turn for the identification of potential therapeutic targets in MRT such as lysyl oxidase and disclosed a platform to identify CSC targets in other rare pediatric tumors for which novel therapeutics are sought.
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影响因子：
3.7
作者：
Bondareva A;Downey CM;Ayres F;Liu W;Boyd SK;Hallgrimsson B;Jirik FR
通讯作者：
Jirik FR
影响因子：
--
作者：
Laidlaw KM;Berhan S;Liu S;Silvestri G;Holyoake TL;Frank DA;Aggarwal B;Bonner MY;Perrotti D;Jørgensen HG;Arbiser JL
通讯作者：
Arbiser JL
影响因子：
4.7
作者：
De Donato, Marta;Petrillo, Marco;Gallo, Daniela
通讯作者：
Gallo, Daniela
影响因子：
--
作者：
Liu N;Cox TR;Cui W;Adell G;Holmlund B;Ping J;Jarlsfelt I;Erler JT;Sun XF
通讯作者：
Sun XF
影响因子：
64.8
作者：
Cox TR;Rumney RMH;Schoof EM;Perryman L;Høye AM;Agrawal A;Bird D;Latif NA;Forrest H;Evans HR;Huggins ID;Lang G;Linding R;Gartland A;Erler JT
通讯作者：
Erler JT