Physiological Chemistry, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany.
The Xiphophorus Genetic Stock Center, Department of Chemistry and Biochemistry, 419 Centennial Hall, Texas State University, San Marcos, TX 78666.
G3 (Bethesda). 2019 Jul 9;9(7):2267-2276. doi: 10.1534/g3.119.400051.
Small aquarium fish models provide useful systems not only for a better understanding of the molecular basis of many human diseases, but also for first-line screening to identify new drug candidates. For testing new chemical substances, current strategies mostly rely on easy to perform and efficient embryonic screens. Cancer, however, is a disease that develops mainly during juvenile and adult stage. Long-term treatment and the challenge to monitor changes in tumor phenotype make testing of large chemical libraries in juvenile and adult animals cost prohibitive. We hypothesized that changes in the gene expression profile should occur early during anti-tumor treatment, and the disease-associated transcriptional change should provide a reliable readout that can be utilized to evaluate drug-induced effects. For the current study, we used a previously established medaka melanoma model. As proof of principle, we showed that exposure of melanoma developing fish to the drugs cisplatin or trametinib, known cancer therapies, for a period of seven days is sufficient to detect treatment-induced changes in gene expression. By examining whole body transcriptome responses we provide a novel route toward gene panels that recapitulate anti-tumor outcomes thus allowing a screening of thousands of drugs using a whole-body vertebrate model. Our results suggest that using disease-associated transcriptional change to screen therapeutic molecules in small fish model is viable and may be applied to pre-clinical research and development stages in new drug discovery.
小型水族馆鱼类模型不仅为更好地理解许多人类疾病的分子基础提供了有用的系统，而且还为首次筛选鉴定新的药物候选物提供了系统。对于测试新的化学物质，目前的策略主要依赖于易于执行和高效的胚胎筛选。然而，癌症是一种主要在青少年和成年期发展的疾病。长期治疗和监测肿瘤表型变化的挑战使得在青少年和成年动物中测试大型化学文库变得代价高昂。我们假设，在抗肿瘤治疗过程中，基因表达谱应该会早期发生变化，并且与疾病相关的转录变化应该提供一个可靠的读数，可以用来评估药物诱导的效果。在目前的研究中，我们使用了先前建立的斑马鱼黑色素瘤模型。作为原理验证，我们表明，将正在发育的黑色素瘤鱼暴露于顺铂或曲美替尼等已知的癌症治疗药物中 7 天足以检测到治疗引起的基因表达变化。通过检查整个机体的转录组反应，我们提供了一种新的途径来重现抗肿瘤结果的基因组合，从而可以使用全脊椎动物模型筛选数千种药物。我们的研究结果表明，使用与疾病相关的转录变化来筛选小鱼模型中的治疗分子是可行的，并且可以应用于新药发现的临床前研究和开发阶段。
