Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma.
Tumor-propagating side population cells are a dynamic subpopulation in undifferentiated pleomorphic sarcoma.
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DOI：
10.1172/jci.insight.148768
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发表时间：
2021-11-22
期刊：
影响因子：
8
通讯作者：
Alman BA
中科院分区：
文献类型：
--
作者：
Tang YJ;Puviindran V;Xiang Y;Yahara Y;Zhang H;Nadesan P;Diao Y;Kirsch DG;Alman BA
肉瘤含有具有增强的肿瘤起始和自我更新特性的肿瘤增殖细胞（TPC）亚群。然而，目前还不清楚肉瘤中的TPC表型是稳定的还是可以从非TPC衍生的动态细胞状态。在这项研究中，我们利用未分化多形性肉瘤（UPS）的小鼠模型，以跟踪肉瘤侧群（SP）细胞，富含TPC和非SP细胞之间的谱系关系。通过共移植SP和非SP细胞表达不同的内源性荧光报告，我们表明，非SP细胞可以产生SP细胞增强体内肿瘤增殖的潜力。使用来自SP和非SP细胞的单细胞RNA测序的谱系轨迹分析支持非SP细胞可以从头呈现SP细胞表型的概念。为了测试根除SP细胞对肿瘤生长和自我更新的影响，我们产生了小鼠肉瘤，其中白喉毒素受体在SP细胞及其后代中表达。使用白喉毒素消融SP群体并不妨碍肿瘤生长或自我更新。总之，我们表明肉瘤SP代表一种动态细胞状态，单独靶向TPC不足以消除肿瘤进展。
Sarcomas contain a subpopulation of tumor-propagating cells (TPCs) with enhanced tumor-initiating and self-renewal properties. However, it is unclear whether the TPC phenotype in sarcomas is stable or a dynamic cell state that can derive from non-TPCs. In this study, we utilized a mouse model of undifferentiated pleomorphic sarcoma (UPS) to trace the lineage relationship between sarcoma side population (SP) cells that are enriched for TPCs and non-SP cells. By cotransplanting SP and non-SP cells expressing different endogenous fluorescent reporters, we show that non-SP cells can give rise to SP cells with enhanced tumor-propagating potential in vivo. Lineage trajectory analysis using single-cell RNA sequencing from SP and non-SP cells supports the notion that non-SP cells can assume the SP cell phenotype de novo. To test the effect of eradicating SP cells on tumor growth and self-renewal, we generated mouse sarcomas in which the diphtheria toxin receptor is expressed in the SP cells and their progeny. Ablation of the SP population using diphtheria toxin did not impede tumor growth or self-renewal. Altogether, we show that the sarcoma SP represent a dynamic cell state and targeting TPCs alone is insufficient to eliminate tumor progression.
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