Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia

Bentley, Victoria L.; Veinotte, Chansey J.; Corkery, Dale; Pinder, Jordan; LeBlanc, Marissa A.; Bedard, Karen; Weng, Andrew P.; Berman, Jason N.; Dellaire, Graham

doi:10.3324/haematol.2014.110742

Cited by 90 publications

(82 citation statements)

References 37 publications

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“…Whilst this can be achieved post-mortem by detecting human-specific antigens using immunocytochemistry ( Bentley et al , 2015), the use of lipophilic fluorescent cell membrane stains in conjunction with zebrafish transgenic lines allows much more data to be collected from animals of greater immaturity. However, quantification of xenografted cancer cell proliferation is equivalent when measured using either membrane stains or fluorescent proteins ( Bentley et al , 2015). …”

Section: Discussionmentioning

confidence: 99%

Embryonic zebrafish xenograft assay of human cancer metastasis

et al. 2018

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Cancer metastasis is the most important prognostic factor determining patient survival, but currently there are very few drugs or therapies that specifically inhibit the invasion and metastasis of cancer cells. Currently, human cancer metastasis is largely studied using transgenic and immunocompromised mouse xenograft models, which are useful for analysing end-point tumour growth but are unable to accurately and reliably monitor in vivo invasion, intravasation, extravasation or secondary tumour formation of human cancer cells. Furthermore, limits in our ability to accurately monitor early stages of tumour growth and detect micro-metastases likely results in pain and suffering to the mice used for cancer xenograft experiments. Zebrafish ( Danio rerio) embryos, however, offer many advantages as a model system for studying the complex, multi-step processes involved during cancer metastasis. This article describes a detailed method for the analysis of human cancer cell invasion and metastasis in zebrafish embryos before they reach protected status at 5 days post fertilisation. Results demonstrate that human cancer cells actively invade within a zebrafish microenvironment, and form metastatic tumours at secondary tissue sites, suggesting that the mechanisms involved during the different stages of metastasis are conserved between humans and zebrafish, supporting the use of zebrafish embryos as a viable model of human cancer metastasis. We suggest that the embryonic zebrafish xenograft model of human cancer is a tractable laboratory model that can be used to understand cancer biology, and as a direct replacement of mice for the analysis of drugs that target cancer invasion and metastasis.

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Section: Discussionmentioning

confidence: 99%

Embryonic zebrafish xenograft assay of human cancer metastasis

et al. 2018

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“…Transplanting malignant patient tissue or cells into hundreds of zebrafish embryos and monitoring the response to planned investigational drug treatments could yield valuable information on the most suitable drug to be administered for that particular patient. Evidence of a response to a small-molecule inhibitor might indicate effective targeting of an actionable genetic driver lesion, as we observed for a child with T-ALL who expressed a novel γ-secretase-responsive Notch mutation (Bentley et al, 2013) (V. L. Bentley, C.J.V., D. P. Corkery, J. B. Pinder, M. A. LeBlanc, K. Bedard et al, unpublished results).…”

Section: Clinical Applications Of the Zebrafish Xenotransplantation Pmentioning

confidence: 52%

“…The absence of certain genes in the zebrafish can also be exploited as a means of identifying human xenografted cells from the zebrafish embryo in ex vivo analyses and immunohistochemistry. For example, we have recently used the promyelocytic leukemia (PML) protein, for which the gene is absent in the zebrafish, as a marker of human primary T-cell leukemia cells during ex vivo proliferation analyses (Bentley et al, 2013). Finally, it should be noted that the human tumor xenografts interact with, and in many instances remodel, the host tissue following engraftment; for example, host vasculature can be recruited by tumor xenografts (Zhao et al, 2011).…”

Section: Zebrafish Xenotransplantationmentioning

confidence: 99%

“…When fluorescence cannot be used to mark human cells either because the cells are dividing too rapidly or the drugs being tested are inherently fluorescent (e.g. doxorubin), an immunocytochemical technique can be applied that uses a fluorescent antibody directed against a human protein not conserved in zebrafish (Bentley et al, 2013) (V. L. Bentley, C.J.V., D. P. Corkery, J. B. Pinder, M. A. LeBlanc, K. Bedard et al, unpublished results).…”

Section: Technical Advances In Zebrafish Xenotransplantationmentioning

confidence: 99%

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Hooking the big one: the potential of zebrafish xenotransplantation to reform cancer drug screening in the genomic era

Veinotte

Dellaire

Berman

2014

Disease Models &Amp; Mechanisms

140

104

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The current preclinical pipeline for drug discovery can be cumbersome and costly, which limits the number of compounds that can effectively be transitioned to use as therapies. Chemical screens in zebrafish have uncovered new uses for existing drugs and identified promising new compounds from large libraries. Xenotransplantation of human cancer cells into zebrafish embryos builds on this work and enables direct evaluation of patient-derived tumor specimens in vivo in a rapid and cost-effective manner. The short time frame needed for xenotransplantation studies means that the zebrafish can serve as an early preclinical drug screening tool and can also help personalize cancer therapy by providing real-time data on the response of the human cells to treatment. In this Review, we summarize the use of zebrafish embryos in drug screening and highlight the potential for xenotransplantation approaches to be adopted as a preclinical tool to identify and prioritize therapies for further clinical evaluation. We also discuss some of the limitations of using zebrafish xenografts and the benefits of using them in concert with murine xenografts in drug optimization.

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“…Since much less human material is required to generate a xenograft, establishing zPDXs using tumor biopsy samples can be more feasible than in mice. To the best of our knowledge, at least two studies already reported the generation of zPDX with biopsy samples [118,127]. Importantly, there is no need for cell culture amplification [105,106,118], thus reducing the time and number of artefactual steps required for in vitro adaptation.…”

Section: Advantages Of the Zebrafish Larval Xenograft Modelmentioning

confidence: 99%

Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

Costa

Estrada

Mendes

et al. 2020

Cells

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Cancer frequency and prevalence have been increasing in the past decades, with devastating impacts on patients and their families. Despite the great advances in targeted approaches, there is still a lack of methods to predict individual patient responses, and therefore treatments are tailored according to average response rates. "Omics" approaches are used for patient stratification and choice of therapeutic options towards a more precise medicine. These methods, however, do not consider all genetic and non-genetic dynamic interactions that occur upon drug treatment. Therefore, the need to directly challenge patient cells in a personalized manner remains. The present review addresses the state of the art of patient-derived in vitro and in vivo models, from organoids to mouse and zebrafish Avatars. The predictive power of each model based on the retrospective correlation with the patient clinical outcome will be considered. Finally, the review is focused on the emerging zebrafish Avatars and their unique characteristics allowing a fast analysis of local and systemic effects of drug treatments at the single-cell level. We also address the technical challenges that the field has yet to overcome.The arrival of precision medicine and immunotherapy are giving hope to finally manage cancer treatment. Many advances were made possible due to the discovery of molecular pathways in tumor cells and on their interaction with the surrounding tumor microenvironment (TME) [1], leading to the development of many new therapies. The latest successes in HER2-targeted therapy and the discovery of immune checkpoint inhibitors are great examples of this [2]. However, not all patients respond and many are not eligible for these "new therapies". Thus, nowadays, the majority of patients are still treated with traditional chemo/radiotherapy and surgery according to clinical guidelines, which are developed and approved based on average efficacy rates.As a result of this "one-size-fits-all" approach, treatments may prove to be efficient for some patients but not for others. For example, in the international therapeutic guidelines (NCCN and ESMO) for advanced colorectal cancer (CRC) there are two main chemotherapeutic arms (FOLFOX and FOLFIRI), which show very similar response rates of~50% [3,4]. In other words,~50% of patients respond to treatment while~50% do not. Clinicians do not know in which group patients will fall, as there is no predictive screening test to provide this information. Thus, patients that start with FOLFOX and do not respond change to FOLFIRI, and vice-versa. This applies for CRC and many other cancers, being especially relevant in the metastatic scenario when oncology therapy guidelines reach branch

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Focused chemical genomics using zebrafish xenotransplantation as a pre-clinical therapeutic platform for T-cell acute lymphoblastic leukemia

Cited by 90 publications

References 37 publications

Embryonic zebrafish xenograft assay of human cancer metastasis

Embryonic zebrafish xenograft assay of human cancer metastasis

Hooking the big one: the potential of zebrafish xenotransplantation to reform cancer drug screening in the genomic era

Zebrafish Avatars towards Personalized Medicine—A Comparative Review between Avatar Models

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