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原文献：Ali, Z., Vildevall, M., Rodriguez, G.V. et al. Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer. J Exp Clin Cancer Res 41, 58 (2022).

原文链接：https://doi.org/10.1186/s13046-022-02280-x

癌症患者在治疗效果和肿瘤侵袭性方面体现出高度的个体差别，而这两方面恰恰是影响肿瘤患者生涯的要害所在，因此，准确展望肿瘤转移危害和治疗效果对个体化治疗至关主要[1]。小鼠患者源性异种移植(PDX)模子在展望治疗效果方面体现出很高的准确性，但展望肿瘤侵袭性的要领仍然缺乏。另外，小鼠PDX实验周期较长，难以知足临床个体化治疗的需求[2-4]。

近年来，斑马鱼肿瘤异种移植(zPDX)系统已成为肿瘤学和肿瘤生物学研究中一种强有力的体内增补系统[5,6]。通过移植肿瘤细胞系来天生zCDX模子，已经使我们对驱动早期肿瘤扩散的分子和病理心理事务[7,8]、肿瘤微情形内的相互作用[9,10]以及对药物或治疗的反应[11-13]有了更深入的明确。由于已建设的细胞系可能随着时间的推移而爆发表型转变，这些模子主要用于基础研究或早期临床前药物开发。为了更好地坚持患者肿瘤的特征，研究者乐成构建了直接移植患者泉源的肿瘤样本的zPDX模子，并证实该模子能够准确地反应响应患者的肿瘤特征[14-19]。

本研究开发了一种新的、可靠的要领，乐成将非小细胞肺癌（NSCLC）组织植入到斑马鱼幼鱼中建设zPDX模子。该zPDX模子准确地再现了响应小鼠PDX模子和患者自身对紫杉醇和厄洛替尼的反应。主要的是，该zPDX平台展望肿瘤向患者淋投合扩散的敏感性为91%，而展望淋投合无侵占的特异性为62%。

● 主要研究效果 

 1. 比照冻存的组织与单细胞悬液，研究效果显示冻存的患者组织移植乐成率优于冻存的患者单细胞悬液，组织移植乐成率高于80%（图1）。

图1

2、用25例zPDX模子评价厄洛替尼和紫杉醇的肿瘤治疗效果，效果显示厄洛替尼和紫杉醇在zPDX上对NSCLC肿瘤的治疗有用率与真实天下中患者的治疗有用率相似（图2D、E）。与药物评价的金标准小鼠PDX模子比照，zPDX对厄洛替尼和紫杉醇的应答与小鼠PDX高度一致（图2F、G）。

图2

3. 将肿瘤组织举行测序剖析，比照与药物治疗相关的靶点后发明，厄洛替尼和紫杉醇在zPDX上的治疗效果与基因检测效果相似（图3）。

图3

4、将爆发转移和未爆发转移患者的肿瘤组织移植至斑马鱼，实验效果显示zPDX模子展望肿瘤向患者淋投合扩散的敏感性为91%，而展望淋投合无侵占的特异性为62%（图4），提醒zPDX模子可准确展望患者体内肿瘤转移的爆发。

图4

环特生物作为斑马鱼手艺应用向导者，深度挖掘、立异斑马鱼手艺的应用场景，在原有斑马鱼CDX模子用于抗肿瘤药物药效评价的基础上，乐成建设多种实体瘤斑马鱼PDX药敏评价系统，实现临床应用，为患者提供精准的用药指导。同时，我们起劲举行基于真实天下肿瘤患者的临床研究，团结浙江大学隶属第二医院开展全天下首个胃癌斑马鱼PDX与患者治疗效果的一致性评价项目（Clinical Trials注册号：NCT05616533，为斑马鱼PDX的临床应用提供越发充分的科学依据。

参考资料：

1. Eberhardt WE, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol. 2015;26:1573–88.

2. Hidalgo M, et al. Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014;4:998–1013.

3. Schueler J, et al. Patient derived renal cell carcinoma xenografts exhibit distinct sensitivity patterns in response to antiangiogenic therapy and constitute a suitable tool for biomarker development. Oncotarget. 2018;9:30946–61.

4. Schueler J, et al. Induction of Acquired Resistance towards EGFR Inhibitor Gefitinib in a Patient-Derived Xenograft Model of Non-Small Cell Lung Cancer and Subsequent Molecular Characterization. Cells. 2019;8(7):740.

5. Rouhi P, et al. Hypoxia-induced metastasis model in embryonic zebrafish. Nat Protoc. 2010;5:1911–8.

6. Xiao J, Glasgow E, Agarwal S. Zebrafish Xenografts for Drug Discovery and Personalized Medicine. Trends Cancer. 2020;6:569–79.

7. Liu C, et al. A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis. Clin Cancer Res. 2017;23:4769–79.

8. Svensson S, et al. CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer. Clin Cancer Res. 2015;21:3794–805.

9. Vazquez Rodriguez G, Abrahamsson A, Jensen LD, Dabrosin C. Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils. Cancer Immunol Res. 2017;5:234–47.

10. Vazquez Rodriguez G, Abrahamsson A, Jensen LDE, Dabrosin C. Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8. Front Immunol. 2018;9:1767.

11. He X, et al. Visualization of human T lymphocyte-mediated eradication of cancer cells in vivo. Proc Natl Acad Sci U S A. 2020;117:22910–9.

12. Kabakci Z, et al. Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression. Sci Rep. 2019;9:1335.

13. Selvaraju K, et al. Cytotoxic unsaturated electrophilic compounds commonly target the ubiquitin proteasome system. Sci Rep. 2019;9:9841.

14. Fior R, et al. Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts. Proc Natl Acad Sci U S A. 2017;114:E8234–43.

15. Gaudenzi G, et al. Patient-derived xenograft in zebrafish embryos: a new platform for translational research in neuroendocrine tumors. Endocrine. 2017;57:214–9.

16. Gaudenzi G, et al. Patient-derived xenograft in zebrafish embryos: a new platform for translational research in neuroendocrine tumors. Endocrine. 2017;57:214–9.

17. Wu JQ, et al. Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer. J Exp Clin Cancer Res. 2017;36:160.

18. Lin J, et al. A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy. Blood. 2016;128:249–52.

19. Costa B, et al. Developments in zebrafish avatars as radiotherapy sensitivity reporters - towards personalized medicine. EBioMedicine. 2020;51:102578.