Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma  

作　　者：Li Wang Xiaojia Huang Xinru You Tianqi Yi Bing Lu Jiali Liu Guohao Lu Minglin Ma Changye Zou Jun Wu Wei Zhao 

机构地区：[1]RNA Biomedical Institute,Sun Yat-Sen Memorial Hospital,Sun Yat-Sen University,Guangzhou 510120,China [2]Key Laboratory of Stem Cells and Tissue Engineering(Sun Yat-Sen University),Ministry of Education,Guangzhou,China [3]School of Biomedical Engineering,Sun Yat-sen University,Guangzhou 510006,China [4]Department of Biological and Environmental Engineering,Cornell University,Ithaca,NY 14853,USA [5]Musculoskeletal Oncology Center,The First Affiliated Hospital of Sun Yat-Sen University,Guangzhou 510080,China [6]Research Institute of Sun Yat-Sen University in Shenzhen,Shenzhen 518057,China

出　　处：《Signal Transduction and Targeted Therapy》2020年第1期684-696,共13页信号转导与靶向治疗（英文）

基　　金：supported by National Natural Science Foundation of China(81972651,51973243,81972507,and 31771630);National Science and Technology Major Project of the Ministry of Science and Technology of China(2018ZX10301402);International Cooperation and Exchange of the National Natural Science Foundation of China(51820105004);Guangdong Innovative and Entrepreneurial Research Team Program(2013S086 and 2016ZT06S029);Natural Science Foundation of Guangdong Province(2017A030312009);Science and Technology Planning Project of Shenzhen(JCYJ20170307141438157).

摘　　要：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.

关 键 词：OSTEOSARCOMA PROGENITOR SYNERGISTIC 

分 类 号：R738[医药卫生—肿瘤]