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Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine.
EBioMedicine ( IF 9.7 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.ebiom.2019.11.039
Bruna Costa 1 , Susana Ferreira 1 , Vanda Póvoa 1 , Maria João Cardoso 2 , Sandra Vieira 2 , Joep Stroom 2 , Paulo Fidalgo 3 , Ricardo Rio-Tinto 3 , Nuno Figueiredo 3 , Oriol Parés 2 , Carlo Greco 2 , Miguel Godinho Ferreira 4 , Rita Fior 1
Affiliation  

BACKGROUND Whereas the role of neoadjuvant radiotherapy in rectal cancer is well-established, the ability to discriminate between radioresistant and radiosensitive tumors before starting treatment is still a crucial unmet need. Here we aimed to develop an in vivo test to directly challenge living cancer cells to radiotherapy, using zebrafish xenografts. METHODS We generated zebrafish xenografts using colorectal cancer cell lines and patient biopsies without in vitro passaging, and developed a fast radiotherapy protocol consisting of a single dose of 25 Gy. As readouts of the impact of radiotherapy we analyzed proliferation, apoptosis, tumor size and DNA damage. FINDINGS By directly comparing isogenic cells that only differ in the KRASG13D allele, we show that it is possible to distinguish radiosensitive from radioresistant tumors in zebrafish xenografts, even in polyclonal tumors, in just 4 days. Most importantly, we performed proof-of-concept experiments using primary rectum biopsies, where clinical response to neoadjuvant chemoradiotherapy correlates with induction of apoptosis in their matching zebrafish Patient-Derived Xenografts-Avatars. INTERPRETATION Our work opens the possibility to predict tumor responses to radiotherapy using the zebrafish Avatar model, sparing valuable therapeutic time and unnecessary toxicity.

中文翻译:

斑马鱼头像作为放射疗法敏感性报告者的发展-面向个性化医学。

背景技术尽管新辅助放射疗法在直肠癌中的作用已得到公认,但是在开始治疗之前区分放射线敏感性和放射敏感性肿瘤的能力仍然是关键的未满足的需求。在这里,我们旨在开发一种体内测试,以使用斑马鱼异种移植物直接挑战活的癌细胞进行放射治疗。方法我们使用结直肠癌细胞系和患者活检样品在没有体外传代的情况下生成了斑马鱼异种移植物,并开发了由25 Gy单剂量组成的快速放疗方案。作为放射疗法影响的读数,我们分析了增殖,凋亡,肿瘤大小和DNA损伤。通过直接比较仅在KRASG13D等位基因上不同的同基因细胞,我们表明,仅用4天的时间,就可以将斑马鱼异种移植物中的放射敏感性和放射敏感性肿瘤区分开来,即使在多克隆肿瘤中也是如此。最重要的是,我们使用原发性直肠活检进行了概念验证实验,其中对新辅助放化疗的临床反应与其在其匹配的斑马鱼患者来源的异种移植物头像中的凋亡诱导相关。解释我们的工作为使用斑马鱼头像模型预测肿瘤对放疗的反应提供了可能性,从而节省了宝贵的治疗时间和不必要的毒性。对新辅助放化疗的临床反应与其诱导的匹配的斑马鱼患者来源的异种移植物头像的凋亡诱导相关。解释我们的工作为使用斑马鱼头像模型预测肿瘤对放疗的反应提供了可能性,从而节省了宝贵的治疗时间和不必要的毒性。对新辅助放化疗的临床反应与其诱导的匹配的斑马鱼患者来源的异种移植物头像的凋亡诱导相关。解释我们的工作为使用斑马鱼头像模型预测肿瘤对放疗的反应提供了可能性,从而节省了宝贵的治疗时间和不必要的毒性。
更新日期:2019-12-18
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