Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma.
Single-cell analysis and functional characterization uncover the stem cell hierarchies and developmental origins of rhabdomyosarcoma.
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DOI：
10.1038/s43018-022-00414-w
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发表时间：
2022-08
期刊：
影响因子：
22.7
通讯作者：
Langenau, David M.
中科院分区：
文献类型：
--
作者：
Wei, Yun;Qin, Qian;Yan, Chuan;Hayes, Madeline N.;Garcia, Sara P.;Xi, Haibin;Do, Daniel;Jin, Alexander H.;Eng, Tiffany C.;McCarthy, Karin M.;Adhikari, Abhinav;Onozato, Maristela L.;Spentzos, Dimitrios;Neilsen, Gunnlaugur P.;Iafrate, A. John;Wexler, Leonard H.;Pyle, April D.;Suva, Mario L.;Dela Cruz, Filemon;Pinello, Luca;Langenau, David M.
横纹肌肉瘤（RMS）是一种常见的儿童癌症，与发育中的骨骼肌有共同的特征。然而，与人类肌肉发育和分子定义的肿瘤增殖细胞的鉴定的细胞层次的保护还没有报道。使用单细胞RNA测序，DNA条形码细胞命运映射和功能性干细胞测定，我们发现了RMS和人类肌肉发育中共有的肿瘤细胞层次结构。我们还确定了肿瘤细胞被抑制的常见发育阶段。融合阴性（FN-）RMS类似于在胚胎和胎儿发育中发现的早期肌源性细胞，而融合阳性（FP-）RMS表达在7-7.75周龄时从胚胎向胎儿发育过渡的肌细胞中发现的高度特异性基因程序。FP-RMS也有神经通路丰富的状态，这表明对肌肉谱系层次结构的严格遵守程度较低。最后，我们在FN-RMS中鉴定了一个分子定义的肿瘤传播亚群，该亚群与可以产生肌肉和成骨细胞的双能肌肉间充质祖细胞具有显著的相似性。
Rhabdomyosarcoma (RMS) is a common childhood cancer that shares features with developing skeletal muscle. Yet, the conservation of cellular hierarchy with human muscle development and the identification of molecularly-defined tumor-propagating cells has not been reported. Using single-cell RNA sequencing, DNA-barcode cell fate mapping, and functional stem cell assays, we uncovered shared tumor cell hierarchies in RMS and human muscle development. We also identified common developmental stages at which tumor cells become arrested. Fusion-negative (FN-) RMS resemble early myogenic cells found in embryonic and fetal development, while fusion-positive (FP-) RMS express a highly specific gene program found in muscle cells transiting from embryonic to fetal development at 7-7.75 weeks of age. FP-RMS also have neural-pathway enriched states, suggesting less-rigid adherence to muscle-lineage hierarchies. Finally, we identified a molecularly-defined tumor-propagating subpopulation in FN-RMS that shares remarkable similarity to bi-potent, muscle mesenchyme progenitors that can make both muscle and osteogenic cells.
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影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
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作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
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影响因子：
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作者：
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Mesirov, Jill P.
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作者：
Slemmons KK;Deel MD;Lin YT;Oristian KM;Kuprasertkul N;Genadry KC;Chen PH;Chi JT;Linardic CM
通讯作者：
Linardic CM
影响因子：
11.2
作者：
Linardic, CM;Downie, DL;Counter, CM
通讯作者：
Counter, CM