Korean Cell Line Bank, Laboratory of Cell Biology, Cancer Research Institute, Seoul National University, Seoul, 03080, Korea.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
J Transl Med. 2024 Oct 2;22(1):889. doi: 10.1186/s12967-024-05700-y.
Sarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.
肉瘤是源自间叶组织的恶性肿瘤，尽管在治疗方法（如手术、放疗和化疗）方面取得了进展，但预后仍然较差，阿霉素是其基础治疗方法。对阿霉素的耐药性仍然是治疗优化的一个重大障碍。本研究旨在剖析肉瘤细胞系中阿霉素耐药的分子基础，从而为制定针对性的治疗策略提供指导。在伦理批准的前提下，建立了来自 14 名患者的 18 种肉瘤细胞系，并分为七个亚型。分子、基因组和转录组分析包括全外显子测序、RNA 测序、药物敏感性测定和通路富集研究，以阐明耐药机制。阿霉素敏感性的变化与特定的遗传改变有关，包括 TP53 突变和基因组 11q24.2 等位置的拷贝数变化。转录组谱分析根据核型复杂性将细胞系分为不同的聚类，从而影响药物反应。此外，通路分析强调了 WNT/BETA-CATENIN 和 HEDGEHOG 等信号通路在阿霉素耐药系中的作用。对肉瘤细胞系的全面分子分析揭示了遗传和转录组因素的复杂相互作用，决定了阿霉素耐药性，这突显了在肉瘤治疗中采用个体化医学方法的必要性。对这些耐药机制的进一步研究将有助于开发更有效、定制化的治疗方案。
