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Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 24975

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Special Issue Editors

Dr. Eleanor Y. Chen

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Guest Editor

Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA
Interests: cancer; sarcoma; rhabdomyosarcoma; epigenetic; therapy; zebrafish; xenograft; functional genomics

Dr. Myron Ignatius

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Guest Editor

Greehey Children's Cancer Research Institute, UT Health Sciences Center, 8403 Floyd Curl Drive, San Antonio, Texas, USA

Special Issue Information

Dear Colleagues,

Cancer research utilizing zebrafish and mammalian models has been instrumental in contributing to our understanding of cellular and molecular mechanisms underlying disease initiation and progression. Zebrafish and mammalian models are also powerful tools in therapeutic target testing and discovery. The emergence of new gene editing, imaging, functional genomics, and single cell technologies has enabled exciting discoveries and new research directions at the basic science and translational levels. This Special Issue of Cancers highlights works that apply emerging gene editing, imaging, functional genomics, and single cell technologies in zebrafish or mammalian models to characterize various hallmarks of cancer and identify therapeutic targets in translational settings

Dr. Eleanor Y. Chen
Dr. Myron Ignatius
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

zebrafish
mammalian
model system
functional genomics
imaging
single cell sequencing
hallmarks of cancer
therapeutic target

Published Papers (7 papers)

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Research

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19 pages, 4822 KiB

Open AccessArticle

atm Mutation and Oxidative Stress Enhance the Pre-Cancerous Effects of UHRF1 Overexpression in Zebrafish Livers

by Yousra Ajouaou, Elena Magnani, Bhavani Madakashira, Eleanor Jenkins and Kirsten C. Sadler

Cancers 2023, 15(8), 2302; https://doi.org/10.3390/cancers15082302 - 14 Apr 2023

Viewed by 2776

Abstract

The ataxia-telangiectasia mutated (atm) gene is activated in response to genotoxic stress and leads to activation of the tp53 tumor suppressor gene which induces either senescence or apoptosis as tumor suppressive mechanisms. Atm also serves non-canonical functions in the response to oxidative stress and chromatin reorganization. We previously reported that overexpression of the epigenetic regulator and oncogene Ubiquitin Like with PHD and Ring Finger Domains 1 (UHRF1) in zebrafish hepatocytes resulted in tp53-dependent hepatocyte senescence, a small liver and larval lethality. We investigated the role of atm on UHRF1-mediated phenotypes by generating zebrafish atm mutants. atm^−/− adults were viable but had reduction in fertility. Embryos developed normally but were protected from lethality caused by etoposide or H₂O₂ exposure and failed to fully upregulate Tp53 targets or oxidative stress response genes in response to these treatments. In contrast to the finding that Tp53 prevents the small liver phenotype caused by UHRF1 overexpression, atm mutation and exposure to H₂O₂ further reduced the liver size in UHRF1 overexpressing larvae whereas treatment with the antioxidant N-acetyl cysteine suppressed this phenotype. We conclude that UHRF1 overexpression in hepatocytes causes oxidative stress, and that loss of atm further enhances this, triggering elimination of these precancerous cells, leading to a small liver. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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15 pages, 4795 KiB

Open AccessArticle

α-Ketoglutarate-Mediated DNA Demethylation Sustains T-Acute Lymphoblastic Leukemia upon TCA Cycle Targeting

by Yanwu Wang, Ning Shen, Gervase Spurlin, Sovannarith Korm, Sarah Huang, Nicole M. Anderson, Leah N. Huiting, Hudan Liu and Hui Feng

Cancers 2022, 14(12), 2983; https://doi.org/10.3390/cancers14122983 - 16 Jun 2022

Cited by 7 | Viewed by 2642

Abstract

Despite the development of metabolism-based therapy for a variety of malignancies, resistance to single-agent treatment is common due to the metabolic plasticity of cancer cells. Improved understanding of how malignant cells rewire metabolic pathways can guide the rational selection of combination therapy to circumvent drug resistance. Here, we show that human T-ALL cells shift their metabolism from oxidative decarboxylation to reductive carboxylation when the TCA cycle is disrupted. The α-ketoglutarate dehydrogenase complex (KGDHC) in the TCA cycle regulates oxidative decarboxylation by converting α-ketoglutarate (α-KG) to succinyl-CoA, while isocitrate dehydrogenase (IDH) 1 and 2 govern reductive carboxylation. Metabolomics flux analysis of T-ALL reveals enhanced reductive carboxylation upon genetic depletion of the E2 subunit of KGDHC, dihydrolipoamide-succinyl transferase (DLST), mimicking pharmacological inhibition of the complex. Mechanistically, KGDHC dysfunction causes increased demethylation of nuclear DNA by α-KG-dependent dioxygenases (e.g., TET demethylases), leading to increased production of both IDH1 and 2. Consequently, dual pharmacologic inhibition of the TCA cycle and TET demethylases demonstrates additive efficacy in reducing the tumor burden in zebrafish xenografts. These findings provide mechanistic insights into how T-ALL develops resistance to drugs targeting the TCA cycle and therapeutic strategies to overcome this resistance. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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24 pages, 5340 KiB

Open AccessArticle

Functional Therapeutic Target Validation Using Pediatric Zebrafish Xenograft Models

by Charlotte Gatzweiler, Johannes Ridinger, Sonja Herter, Xenia F. Gerloff, Dina ElHarouni, Yannick Berker, Roland Imle, Lukas Schmitt, Sina Kreth, Sabine Stainczyk, Simay Ayhan, Sara Najafi, Damir Krunic, Karen Frese, Benjamin Meder, David Reuss, Petra Fiesel, Kathrin Schramm, Mirjam Blattner-Johnson, David T. W. Jones, Ana Banito, Frank Westermann, Sina Oppermann, Till Milde, Heike Peterziel, Olaf Witt and Ina Oehme Show full author list Hide full author list

Cancers 2022, 14(3), 849; https://doi.org/10.3390/cancers14030849 - 8 Feb 2022

Cited by 13 | Viewed by 4011

Abstract

The survival rate among children with relapsed tumors remains poor, due to tumor heterogeneity, lack of directly actionable tumor drivers and multidrug resistance. Novel personalized medicine approaches tailored to each tumor are urgently needed to improve cancer treatment. Current pediatric precision oncology platforms, such as the INFORM (INdividualized Therapy FOr Relapsed Malignancies in Childhood) study, reveal that molecular profiling of tumor tissue identifies targets associated with clinical benefit in a subgroup of patients only and should be complemented with functional drug testing. In such an approach, patient-derived tumor cells are exposed to a library of approved oncological drugs in a physiological setting, e.g., in the form of animal avatars injected with patient tumor cells. We used molecularly fully characterized tumor samples from the INFORM study to compare drug screen results of individual patient-derived cell models in functional assays: (i) patient-derived spheroid cultures within a few days after tumor dissociation; (ii) tumor cells reisolated from the corresponding mouse PDX; (iii) corresponding long-term organoid-like cultures and (iv) drug evaluation with the corresponding zebrafish PDX (zPDX) model. Each model had its advantage and complemented the others for drug hit and drug combination selection. Our results provide evidence that in vivo zPDX drug screening is a promising add-on to current functional drug screening in precision medicine platforms. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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21 pages, 4346 KiB

Open AccessArticle

Systematic Roadmap for Cancer Drug Screening Using Zebrafish Embryo Xenograft Cancer Models: Melanoma Cell Line as a Case Study

by Patricia Letrado, Holly Mole, María Montoya, Irene Palacios, Jorge Barriuso, Adam Hurlstone, Roberto Díez-Martínez and Julen Oyarzabal

Cancers 2021, 13(15), 3705; https://doi.org/10.3390/cancers13153705 - 23 Jul 2021

Cited by 1 | Viewed by 3000

Abstract

Zebrafish embryo tumor transplant models are widely utilized in cancer research. Compared with traditional murine models, the small size and transparency of zebrafish embryos combined with large clutch sizes that increase statistical power and cheap husbandry make them a cost-effective and versatile tool for in vivo drug discovery. However, the lack of a comprehensive analysis of key factors impacting the successful use of these models impedes the establishment of basic guidelines for systematic screening campaigns. Thus, we explored the following crucial factors: (i) user-independent inclusion criteria, focusing on sample homogeneity; (ii) metric definition for data analysis; (iii) tumor engraftment criteria; (iv) image analysis versus quantification of human cancer cells using qPCR (RNA and gDNA); (v) tumor implantation sites; (vi) compound distribution (intratumoral administration versus alternative inoculation sites); and (vii) efficacy (intratumoral microinjection versus compound solution in media). Based on these analyses and corresponding assessments, we propose the first roadmap for systematic drug discovery screening in zebrafish xenograft cancer models using a melanoma cell line as a case study. This study aims to help the wider cancer research community to consider the adoption of this versatile model for cancer drug screening projects. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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25 pages, 64458 KiB

Open AccessArticle

Inhibiting Endothelial Cell Function in Normal and Tumor Angiogenesis Using BMP Type I Receptor Macrocyclic Kinase Inhibitors

by Jin Ma, Jiang Ren, Midory Thorikay, Maarten van Dinther, Gonzalo Sanchez-Duffhues, Josselin Caradec, Pascal Benderitter, Jan Hoflack and Peter ten Dijke

Cancers 2021, 13(12), 2951; https://doi.org/10.3390/cancers13122951 - 12 Jun 2021

Cited by 5 | Viewed by 3962

Abstract

Angiogenesis, i.e., the formation of new blood vessels from pre-existing endothelial cell (EC)-lined vessels, is critical for tissue development and also contributes to neovascularization-related diseases, such as cancer. Vascular endothelial growth factor (VEGF) and bone morphogenetic proteins (BMPs) are among many secreted cytokines that regulate EC function. While several pharmacological anti-angiogenic agents have reached the clinic, further improvement is needed to increase clinical efficacy and to overcome acquired therapy resistance. More insights into the functional consequences of targeting specific pathways that modulate blood vessel formation may lead to new therapeutic approaches. Here, we synthesized and identified two macrocyclic small molecular compounds termed OD16 and OD29 that inhibit BMP type I receptor (BMPRI)-induced SMAD1/5 phosphorylation and downstream gene expression in ECs. Of note, OD16 and OD29 demonstrated higher specificity against BMPRI activin receptor-like kinase 1/2 (ALK1/2) than the commonly used small molecule BMPRI kinase inhibitor LDN-193189. OD29, but not OD16, also potently inhibited VEGF-induced extracellular regulated kinase MAP kinase phosphorylation in ECs. In vitro, OD16 and OD29 exerted strong inhibition of BMP9 and VEGF-induced ECs migration, invasion and cord formation. Using Tg (fli:EGFP) zebrafish embryos, we found that OD16 and OD29 potently antagonized dorsal longitudinal anastomotic vessel (DLAV), intra segmental vessel (ISV), and subintestinal vessel (SIV) formation during embryonic development. Moreover, the MDA-MB-231 breast cancer cell-induced tumor angiogenesis in zebrafish embryos was significantly decreased by OD16 and OD29. Both macrocyclic compounds might provide a steppingstone for the development of novel anti-angiogenesis therapeutic agents. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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Review

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28 pages, 1407 KiB

Open AccessReview

What Zebrafish and Nanotechnology Can Offer for Cancer Treatments in the Age of Personalized Medicine

by María Cascallar, Sandra Alijas, Alba Pensado-López, Abi Judit Vázquez-Ríos, Laura Sánchez, Roberto Piñeiro and María de la Fuente

Cancers 2022, 14(9), 2238; https://doi.org/10.3390/cancers14092238 - 30 Apr 2022

Cited by 7 | Viewed by 3856

Abstract

Cancer causes millions of deaths each year and thus urgently requires the development of new therapeutic strategies. Nanotechnology-based anticancer therapies are a promising approach, with several formulations already approved and in clinical use. The evaluation of these therapies requires efficient in vivo models to study their behavior and interaction with cancer cells, and to optimize their properties to ensure maximum efficacy and safety. In this way, zebrafish is an important candidate due to its high homology with the human genoma, its large offspring, and the ease in developing specific cancer models. The role of zebrafish as a model for anticancer therapy studies has been highly evidenced, allowing researchers not only to perform drug screenings but also to evaluate novel therapies such as immunotherapies and nanotherapies. Beyond that, zebrafish can be used as an “avatar” model for performing patient-derived xenografts for personalized medicine. These characteristics place zebrafish in an attractive position as a role model for evaluating novel therapies for cancer treatment, such as nanomedicine. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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18 pages, 1302 KiB

Open AccessReview

Inducible Liver Cancer Models in Transgenic Zebrafish to Investigate Cancer Biology

by Ai Qi Lee, Yan Li and Zhiyuan Gong

Cancers 2021, 13(20), 5148; https://doi.org/10.3390/cancers13205148 - 14 Oct 2021

Cited by 7 | Viewed by 3049

Abstract

Primary liver cancer is one of the most prevalent and deadly cancers, which incidence continues to increase while treatment response remains poor; thus, in-depth understanding of tumour events is necessary to develop more effective therapies. Animal models for liver cancer are powerful tools to reach this goal. Over the past decade, our laboratory has established multiple oncogene transgenic zebrafish lines that can be robustly induced to develop liver cancer. Histological, transcriptomic and molecular analyses validate the use of these transgenic zebrafish as experimental models for liver cancer. In this review, we provide a comprehensive summary of our findings with these inducible zebrafish liver cancer models in tumour initiation, oncogene addiction, tumour microenvironment, gender disparity, cancer cachexia, drug screening and others. Induced oncogene expression causes a rapid change of the tumour microenvironment such as inflammatory responses, increased vascularisation and rapid hepatic growth. In several models, histologically-proven carcinoma can be induced within one week of chemical inducer administration. Interestingly, the induced liver tumours show the ability to regress when the transgenic oncogene is suppressed by the withdrawal of the chemical inducer. Like human liver cancer, there is a strong bias of liver cancer severity in male zebrafish. After long-term tumour progression, liver cancer-bearing zebrafish also show symptoms of cancer cachexia such as muscle-wasting. In addition, the zebrafish models have been used to screen for anti-metastasis drugs as well as to evaluate environmental toxicants in carcinogenesis. These findings demonstrated that these inducible zebrafish liver cancer models provide rapid and convenient experimental tools for further investigation of fundamental cancer biology, with the potential for the discovery of new therapeutic approaches. Full article

(This article belongs to the Special Issue Application of Emerging Technologies in Zebrafish and Mammalian Cancer Models for Disease Characterization and Therapeutic Target Discovery)

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