Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma.
Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma.
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纳米颗粒增强化疗耐药骨肉瘤中单细胞转录组学定义的干样祖细胞联合疗法
DOI：
10.1038/s41392-020-00248-x
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发表时间：
2020-09-25
影响因子：
39.3
通讯作者：
Zhao W
中科院分区：
文献类型：
--
作者：
Wang L;Huang X;You X;Yi T;Lu B;Liu J;Lu G;Ma M;Zou C;Wu J;Zhao W
骨肉瘤细胞对治疗压力的适应阻碍了骨肉瘤化疗的疗效。然而，骨肉瘤肿瘤中治疗抗性细胞的特征和细胞组织仍然难以捉摸。在这里，我们利用单细胞转录组学系统地映射在化疗耐药骨肉瘤肿瘤的细胞类型特异性基因表达。我们的数据表明，VEGFR 2-JMJD 3丰富的子集作为静止的干细胞样细胞，从而建立了骨肉瘤中治疗抗性活跃循环祖细胞库（JMJD 3丰富）的层次结构。VEGFR 2抑制剂和JMJD 3抑制剂协同抑制骨肉瘤细胞增殖和肿瘤生长。虽然骨肉瘤细胞倾向于通过内质网（ER）应激激活CHOP促凋亡因子而由协同疗法诱导的凋亡，但干细胞样/祖细胞表现出适应性反应，导致其存活。用谷胱甘肽合成抑制剂处理引起的干细胞样/祖细胞中细胞谷胱甘肽水平的降低增加了ER应激诱导的细胞凋亡。重要的是，针对干细胞样/祖细胞的协同治疗的显著治疗改善是通过使用谷胱甘肽清除纳米颗粒实现的，其可以有效地装载和释放药物对。总的来说，我们的研究为理解谷胱甘肽信号传导作为干细胞样/祖细胞的治疗弱点之一提供了一个框架。总的来说，这些发现揭示了一个有希望的武器库，通过封装谷胱甘肽清除纳米颗粒与共靶向VEGFR 2和JMJD 3来根除化疗耐药性骨肉瘤。
The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.
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影响因子：
37.3
作者：
Pignochino Y;Capozzi F;D'Ambrosio L;Dell'Aglio C;Basiricò M;Canta M;Lorenzato A;Vignolo Lutati F;Aliberti S;Palesandro E;Boccone P;Galizia D;Miano S;Chiabotto G;Napione L;Gammaitoni L;Sangiolo D;Benassi MS;Pasini B;Chiorino G;Aglietta M;Grignani G
通讯作者：
Grignani G
影响因子：
9.7
作者：
Bi, Yiming;Li, Han;Zhao, Gang
通讯作者：
Zhao, Gang
影响因子：
5.2
作者：
Roidl, Deborah;Hellbach, Nicole;Vogel, Tanja
通讯作者：
Vogel, Tanja
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1016/j.biocel.2019.01.015
发表时间：
2019-04-01
影响因子：
4
作者：
Ghasemi, Faezeh;Sarabi, Parisa Zia;Esmaeilzadeh, Abdolreza
通讯作者：
Esmaeilzadeh, Abdolreza