Weinman Marcus A, Ramsey Stephen A, Leeper Haley J, Brady Jacqueline V, Schlueter Andrew, Stanisheuski Stanislau, Maier Claudia S, Miller Tasha, Ruby Carl E, Bracha Shay
University of Vermont, Burlington, USA.
Oregon State University, Corvallis, USA.
Cancer Cell Int. 2021 May 1;21(1):245. doi: 10.1186/s12935-021-01943-7.
Osteosarcoma patients often experience poor outcomes despite chemotherapy treatment, likely due in part to various mechanisms of tumor cell innate and/or acquired drug resistance. Exosomes, microvesicles secreted by cells, have been shown to play a role in drug resistance, but a comprehensive protein signature relating to osteosarcoma carboplatin resistance has not been fully characterized.
In this study, cell lysates and exosomes from two derivatives (HMPOS-2.5R and HMPOS-10R) of the HMPOS osteosarcoma cell line generated by repeated carboplatin treatment and recovery, were characterized proteomically by mass spectrometry. Protein cargos of circulating serum exosomes from dogs with naturally occurring osteosarcoma, were also assessed by mass spectrometry, to identify biomarkers that discriminate between good and poor responders to carboplatin therapy.
Both cell lysates and exosomes exhibited distinct protein signatures related to drug resistance. Furthermore, exosomes from the resistant HMPOS-2.5R cell line were found to transfer drug resistance to drug-sensitive HMPOS cells. The comparison of serum exosomes from dogs with a favorable disease-free interval [DFI] of > 300 days, and dogs with < 100 days DFI revealed a proteomic signature that could discriminate between the two cohorts with high accuracy. Furthermore, when the patient's exosomes were compared to exosomes isolated from carboplatin resistant cell lines, several putative biomarkers were found to be shared.
The findings of this study highlight the significance of exosomes in the potential transfer of drug resistance, and the discovery of novel biomarkers for the development of liquid biopsies to better guide personalized chemotherapy treatment.
骨肉瘤患者尽管接受了化疗，但预后往往较差，这可能部分归因于肿瘤细胞先天性和/或获得性耐药的多种机制。细胞分泌的微囊泡外泌体已被证明在耐药中起作用，但与骨肉瘤顺铂耐药相关的全面蛋白质特征尚未完全明确。
在本研究中，通过质谱对由反复顺铂处理和恢复产生的HMPOS骨肉瘤细胞系的两种衍生物（HMPOS-2.5R和HMPOS-10R）的细胞裂解物和外泌体进行了蛋白质组学表征。还通过质谱评估了患有自然发生的骨肉瘤的犬的循环血清外泌体的蛋白质含量，以鉴定区分顺铂治疗反应良好和反应不佳的生物标志物。
细胞裂解物和外泌体均表现出与耐药相关的独特蛋白质特征。此外，发现来自耐药性HMPOS-2.5R细胞系的外泌体将耐药性转移至药物敏感的HMPOS细胞。对无病生存期[DFI]>300天的犬和DFI<100天的犬的血清外泌体进行比较，发现了一种蛋白质组学特征，可高精度地区分这两个队列。此外，当将患者的外泌体与从顺铂耐药细胞系中分离的外泌体进行比较时，发现了几种推定的生物标志物。
本研究结果突出了外泌体在耐药性潜在转移中的重要性，以及发现用于开发液体活检以更好地指导个性化化疗治疗的新型生物标志物。
