State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology (ECUST), Shanghai, People's Republic of China.
Qingdao Innovation Institute of East China University of Science and Technology, Shanghai, People's Republic of China.
Biotechnol J. 2024 Sep;19(9):e2400163. doi: 10.1002/biot.202400163.
The 3D multicellular tumor spheroid (MTS) model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the 2D monolayer model. In this study, we used multiomics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization, and mitochondrial function. An integrated analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, seven genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4, and SLC2A1, exhibited significant upregulation. Conversely, four genes, COA7, DLD, IFNGR1, and QRSL1, were significantly downregulated. Clinical prognostic analysis using the TCGA survival database indicated that high-expression groups of SLC2A1, ALDOC, and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.
三维多细胞肿瘤球体（MTS）模型在复制肿瘤微环境方面具有更高的逼真度，并表现出对临床药物的异常耐药性，与 2D 单层模型相比。在这项研究中，我们使用多组学（转录组、蛋白质组学和代谢组学）工具来探索两种培养模型的分子机制和代谢差异。基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集途径分析表明，两种培养模型之间差异表达的基因主要富集在与细胞外基质、细胞外结构组织和线粒体功能相关的细胞成分和生物学过程中。对三种组学数据的综合分析揭示了 11 个可能的耐药靶标。在这些靶标中，有 7 个基因，AKR1B1、ALDOC、GFPT2、GYS1、LAMB2、PFKFB4 和 SLC2A1，表达显著上调。相反，有 4 个基因，COA7、DLD、IFNGR1 和 QRSL1，表达显著下调。使用 TCGA 生存数据库进行临床预后分析表明，SLC2A1、ALDOC 和 PFKFB4 的高表达组与患者的生存呈显著负相关。我们进一步验证了它们在化疗药物耐药中的作用，表明它们在改善预后和化疗结果方面具有潜在意义。这些结果为潜在的治疗靶点提供了有价值的见解，可能提高治疗效果和患者预后。
