Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma
| Autor: | Xinru You, Li Wang, Jun Wu, Changye Zou, Wei Zhao, Jiali Liu, Bing Lu, Guohao Lu, Minglin Ma, Tianqi Yi, Xiaojia Huang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Cell lcsh:Medicine Mice Nude Bone Neoplasms CHOP Article Mice 03 medical and health sciences 0302 clinical medicine Single-cell analysis Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Bone cancer Genetics medicine Animals Humans Progenitor cell lcsh:QH301-705.5 Progenitor Mice Inbred BALB C Osteosarcoma Cancer stem cells Chemistry Gene Expression Profiling lcsh:R medicine.disease Xenograft Model Antitumor Assays 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) Drug Resistance Neoplasm Cell culture Apoptosis 030220 oncology & carcinogenesis Drug delivery Neoplastic Stem Cells Cancer research Nanoparticles Female Single-Cell Analysis |
| Zdroj: | Signal Transduction and Targeted Therapy Signal Transduction and Targeted Therapy, Vol 5, Iss 1, Pp 1-13 (2020) |
| ISSN: | 2059-3635 |
| DOI: | 10.1038/s41392-020-00248-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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