The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an “epithelial cell like” signature while SAHA favored a “mesenchymal cell like” one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment.

中文翻译：

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超声和转录组学确定顺铂和组蛋白脱乙酰化对患者体内胃癌模型中肿瘤结构和微环境的不同影响


基于过渡金属的化疗（例如顺铂）或靶向治疗（例如组蛋白脱乙酰酶抑制剂，HDACi）对胃癌（GC）疗效不佳的原因仍然难以捉摸，最近的研究表明肿瘤微环境可能导致耐药性。因此，我们的目标是通过建立患者来源的 GC 异种移植物并结合超声、免疫组织化学和转录组学，获得有关顺铂和泛 HDACi SAHA（次苯异羟肟酸）对 GC 肿瘤亚结构和微环境影响的信息来分析。肿瘤对 SAHA 和顺铂有部分反应。超声波可以比卡尺更准确地测量肿瘤。重要的是，超声可以无创地实时访问肿瘤亚结构，显示顺铂和 SAHA 之间的差异。这些差异通过肿瘤微环境的免疫组织化学和转录组分析、识别特定细胞类型特征和转录因子激活得到证实。例如，顺铂诱导“上皮细胞样”特征，而 SAHA 则偏向“间充质细胞样”特征。总而言之，超声波可以精确跟踪肿瘤进展，同时能够无创地实时访问肿瘤底层结构。结合转录组学，我们的结果强调了两种药物引起的不同的肿瘤内结构变化，对肿瘤微环境的影响不同。