A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy

Lin, Jianhong; Zhang, Weihong; Zhao, Jian; Kwart, Ariel; Yang, Chun; Ma, Dongdong; Ren, Xiubao; Tai, Yu Tzu; Anderson, Kenneth C.; Handin, Robert I.; Munshi, Nikhil C.

doi:10.1182/blood-2016-03-704460

Cited by 63 publications

(58 citation statements)

References 13 publications

(12 reference statements)

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“…Therefore, zPDX models are more suitable for high‐throughput studies, which can yield greater statistical power and possibly identify previously undetectable subclones (e.g., drug‐tolerant subclones) . Furthermore, zPDX models could better preserve information of the parental tumors as patient‐derived cells could be used immediately after cell dissociation rather than at Passage 3 or later, which is common for murine PDX tumors . Recent studies have also suggested a variety of alternatives for model selection, and some have potential to become next‐generation preclinical cancer models.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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Patient‐derived xenograft (PDX) models are widely used as preclinical cancer models and are considered better than cell culture models in recapitulating the histological features, molecular characteristics and intratumoral heterogeneity (ITH) of human tumors. While the PDX model is commonly accepted for use in drug discovery and other translational studies, a growing body of evidence has suggested its limitations. Recently, the fidelity of cancer cells within a PDX has been questioned, which may impede the future application of these models. In this review, we will focus the variable phenotypes of xenograft tumors and the genomic instability and molecular inconsistency of PDX tumors after serial transplantation. Next, we will discuss the underlying mechanism of ITH and its clinical relevance. Stochastic selection bias in the sampling process and/or deterministic clonal dynamics due to murine selective pressure may have detrimental effects on the results of personalized medicine and drug screening studies. In addition, we aim to identify a possible solution for the issue of fidelity in current PDX models and to discuss emerging next‐generation preclinical models.

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Section: Conclusion and Perspectivementioning

confidence: 99%

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

Shi

Jia

et al. 2019

Intl Journal of Cancer

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“…These authors were the first to show in a retrospective study that zPDXs can be a predictive tool for co-clinical assays. In this study, zPDXs were treated with bortezomib and lenalidomide, and showed a response equivalent to patient's clinical outcome: sensitive tumors responded, whilst metastatic tumors did not, similarly to what was observed in patients (n = 6 patients) [112]. Subsequent work from Wu J.Q.…”

Section: Zebrafish Patient-derived (Zpdx)-avatarsmentioning

confidence: 74%

“…Since then, several zebrafish xenograft studies have been developed mostly with commercially available cell lines, derived from a wide range of cancer types, such as breast cancer, leukemia, lung cancer, CRC, pancreatic cancer, stomach cancer, glioblastoma, and melanoma (Table S1). This model has been successfully established to investigate several hallmarks of cancer, in particular angiogenesis [104,[106][107][108][109][110][111][112], cancer cell invasion/extravasion [113][114][115], and micrometastasis formation [106,114,116] (Table S1). In addition, there are already several studies that use the zebrafish xenograft model in the process of drug discovery and pre-clinical evaluation of different types of therapies, such as chemotherapy, radiotherapy [117,118] and biological therapies [106] (Table S1).…”

Section: Pioneersmentioning

confidence: 99%

“…Both types of samples showed invasive and metastatic behaviors, with cells disseminating through the whole zebrafish, suggesting that this is a good model to investigate tumor invasiveness and metastatic potential [105]. In 2016, Lin et al showed that it is possible to generate zPDXs from multiple myeloma cells by injecting in the PVS rather than in the yolk sac, with engraftment rates of approximately 80% [112]. These authors were the first to show in a retrospective study that zPDXs can be a predictive tool for co-clinical assays.…”

Section: Zebrafish Patient-derived (Zpdx)-avatarsmentioning

confidence: 99%

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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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“…Also, various human tumor cell lines, including melanoma, glioma, hepatoma, lung cancer, pancreatic cancer, ovarian carcinomas, breast cancer, prostate cancer, retinoblastoma, and leukemia, have been xenotransplanted into zebrafish 18 to study several aspects of tumorigenesis, like tumor cell migration, angiogenesis, extravasation, and micrometastases [19][20][21][22][23] . Most importantly, proof-of-concept studies have suggested that xenogeneic tumor transplant models using zebrafish embryos can be used as a screening platform to identify novel therapeutic compounds and approaches [24][25][26][27] . However, long-term, high resolution, timelapse images of such transplanted tumor cells are lacking, and their behavior in circulation has not been continuously monitored.…”

mentioning

confidence: 99%

Continuous high-resolutionin vivoimaging reveals tumor-specific dissemination in an embryonic zebrafish xenograft model

Asokan

Daetwyler

Bernas

et al. 2017

Preprint

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Mechanisms mediating tumor metastasis are crucial for diagnostic and therapeutic targeting. Here, we take advantage of a transparent embryonic zebrafish xenograft model (eZXM) to visualize and track injected human leukemic and breast cancer cells in real time using selective plane illumination microscopy (SPIM) for up to 30 hours. Injected cells exhibited disease-specific patterns of intravascular distribution with leukemic cells moving faster than breast cancer cells. While breast cancer cells predominantly adhered to nearby regions, about 30% invaded the avascularized tissue, reminiscent of their metastatic phenotype. Survival of the injected tumor cells was partly inhibited by the cellular innate immune system of the recipient embryos and leukemic cell dissemination was effectively inhibited by pharmacological ROCK1 blockade. These observations, and the ability to image several embryos simultaneously, support the use of eZXM and SPIM imaging as a functional screening platform to identify compounds that restricts cancer cell spread and invasion.

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A clinically relevant in vivo zebrafish model of human multiple myeloma to study preclinical therapeutic efficacy

Abstract: Key Points MM cell lines and primary MM cells can be engrafted and grown in vivo in Casper zebrafish larvae. The zebrafish MM in vivo xenograft model can be used as a pretreatment drug-sensitivity prediction platform for MM patients.

Cited by 63 publications

References 13 publications

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

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

Continuous high-resolutionin vivoimaging reveals tumor-specific dissemination in an embryonic zebrafish xenograft model

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