scholarly journals Zebrafish as a model to investigate the effects of exercise in cancer

2018 ◽  
Author(s):  
Alexandra Yin ◽  
Nathaniel R. Campbell ◽  
Lee W. Jones ◽  
Richard M. White
Keyword(s):  
Endurance Exercise ◽  
Large Scale ◽  
Flow Chamber ◽  
Model Systems ◽  
Zebrafish Model ◽  
Cancer Pathogenesis ◽  
Cancer Models ◽  
Key Aspects ◽  
Response To Exercise

AbstractEmerging data indicates that exercise may regulate cancer pathogenesis, but the mechanisms underpinning how it regulates the tumor as well as surrounding microenvironment are poorly understood. Dissecting this complex, highly integrated physiology requires model systems which accurately recapitulate key aspects of human response to exercise, yet permit rapid and unbiased genetic interrogation of relevant pathways. The zebrafish has emerged as a new model for cancer due to its high resolution in vivo imaging and capacity for large-scale, unbiased screening approaches. Here, we have developed a set of tools to study the effects of exercise in a zebrafish model of melanoma. Using a flow chamber, we studied the effects of endurance exercise bouts (3-6 hour/d, 5d/wk for 1 to 3 wks) in both larval and adult zebrafish. The regimen was well tolerated, with no unexpected toxicities or changes in survival. When the zebrafish were transplanted with ZMEL1-GFP melanoma cells, we found that endurance exercise over a 2-week period led to a significant decrease in cancer growth in the larval zebrafish. As zebrafish cancer models show strong conservation in human disease, our findings have direct application to understanding the human exercise/cancer relationship.

Tumor spheroids and organoids as preclinical model systems

2021 ◽  
Vol 33 (3) ◽  
pp. 229-234
Author(s):  
Aria Baniahmad
Keyword(s):  
Apoptotic Cell ◽  
Model Systems ◽  
Adherent Cell ◽  
Preclinical Model ◽  
Cancer Tissue ◽  
Tumor Spheroids ◽  
Cancer Models ◽  
Cancer Multiple ◽  
Cell Cell

Abstract The generation of three-dimensional (3D) cancer models is a novel and fascinating development in the study of personalized medicine and tumor-specific drug delivery. In addition to the classical two-dimensional (2D) adherent cell culture models, 3D spheroid and organoid cancer models that mimic the microenvironment of cancer tissue are emerging as an important preclinical model system. 3D cancer models form, similar to cancer, multiple cell–cell and cell–extracellular matrix interactions and activate different cellular cascades/pathways, like proliferation, quiescence, senescence, and necrotic or apoptotic cell death. Further, it is possible to analyze genetic variations and mutations, the microenvironment of cell–cell interactions, and the uptake of therapeutics and nanoparticles in nanomedicine. Important is also the analysis of cancer stem cells (CSCs), which could play key roles in resistance to therapy and cancer recurrence. Tumor spheroids can be generated from one tumor-derived cell line or from co-culture of two or more cell lines. Tumor organoids can be derived from tumors or may be generated from CSCs that differentiate into multiple facets of cancerous tissue. Similarly, tumorspheres can be generated from a single CSC. By transplanting spheroids and organoids into immune-deficient mice, patient-derived xenografts can serve as a preclinical model to test therapeutics in vivo. Although the handling and analysis of 3D tumor spheroids and organoids is more complex, it will provide insights into various cancer processes that cannot be provided by 2D culture. Here a short overview of 3D tumor systems as preclinical models is provided.

scholarly journals Zebrafish Cancer Predisposition Models

2021 ◽  
Vol 9 ◽  
Author(s):  
Kim Kobar ◽  
Keon Collett ◽  
Sergey V. Prykhozhij ◽  
Jason N. Berman
Keyword(s):  
Large Scale ◽  
Genetic Manipulation ◽  
Bone Marrow Failure ◽  
Cancer Predisposition ◽  
Potential Candidate ◽  
Cancer Evolution ◽  
High Fecundity ◽  
Cancer Models ◽  
The Impact

Cancer predisposition syndromes are rare, typically monogenic disorders that result from germline mutations that increase the likelihood of developing cancer. Although these disorders are individually rare, resulting cancers collectively represent 5–10% of all malignancies. In addition to a greater incidence of cancer, affected individuals have an earlier tumor onset and are frequently subjected to long-term multi-modal cancer screening protocols for earlier detection and initiation of treatment. In vivo models are needed to better understand tumor-driving mechanisms, tailor patient screening approaches and develop targeted therapies to improve patient care and disease prognosis. The zebrafish (Danio rerio) has emerged as a robust model for cancer research due to its high fecundity, time- and cost-efficient genetic manipulation and real-time high-resolution imaging. Tumors developing in zebrafish cancer models are histologically and molecularly similar to their human counterparts, confirming the validity of these models. The zebrafish platform supports both large-scale random mutagenesis screens to identify potential candidate/modifier genes and recently optimized genome editing strategies. These techniques have greatly increased our ability to investigate the impact of certain mutations and how these lesions impact tumorigenesis and disease phenotype. These unique characteristics position the zebrafish as a powerful in vivo tool to model cancer predisposition syndromes and as such, several have already been created, including those recapitulating Li-Fraumeni syndrome, familial adenomatous polyposis, RASopathies, inherited bone marrow failure syndromes, and several other pathogenic mutations in cancer predisposition genes. In addition, the zebrafish platform supports medium- to high-throughput preclinical drug screening to identify compounds that may represent novel treatment paradigms or even prevent cancer evolution. This review will highlight and synthesize the findings from zebrafish cancer predisposition models created to date. We will discuss emerging trends in how these zebrafish cancer models can improve our understanding of the genetic mechanisms driving cancer predisposition and their potential to discover therapeutic and/or preventative compounds that change the natural history of disease for these vulnerable children, youth and adults.

scholarly journals Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

2020 ◽  
Vol 117 (48) ◽  
pp. 30670-30678
Author(s):  
Olivera Grbovic-Huezo ◽  
Kenneth L. Pitter ◽  
Nicolas Lecomte ◽  
Joseph Saglimbeni ◽  
Gokce Askan ◽  
...  
Keyword(s):  
Large Scale ◽  
Single Agent ◽  
Model Systems ◽  
Ductal Adenocarcinoma ◽  
In Vivo Model ◽  
Cancer Therapies ◽  
Hsp90 Inhibition ◽  
Dismal Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, which limits surgical options and portends a dismal prognosis. Current oncologic PDAC therapies confer marginal benefit and, thus, a significant unmet clinical need exists for new therapeutic strategies. To identify effective PDAC therapies, we leveraged a syngeneic orthotopic PDAC transplant mouse model to perform a large-scale, in vivo screen of 16 single-agent and 41 two-drug targeted therapy combinations in mice. Among 57 drug conditions screened, combined inhibition of heat shock protein (Hsp)-90 and MEK was found to produce robust suppression of tumor growth, leading to an 80% increase in the survival of PDAC-bearing mice with no significant toxicity. Mechanistically, we observed that single-agent MEK inhibition led to compensatory activation of resistance pathways, including components of the PI3K/AKT/mTOR signaling axis, which was overcome with the addition of HSP90 inhibition. The combination of HSP90(i) + MEK(i) was also active in vitro in established human PDAC cell lines and in vivo in patient-derived organoid PDAC transplant models. These findings encourage the clinical development of HSP90(i) + MEK(i) combination therapy and highlight the power of clinically relevant in vivo model systems for identifying cancer therapies.

scholarly journals Models of tendon development and injury

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Sophia K. Theodossiou ◽  
Nathan R. Schiele
Keyword(s):  
Computational Models ◽  
Ex Vivo ◽  
Current Model ◽  
Stem Cell Differentiation ◽  
Tendon Injury ◽  
Model Systems ◽  
Tendon Development ◽  
Key Aspects

AbstractTendons link muscle to bone and transfer forces necessary for normal movement. Tendon injuries can be debilitating and their intrinsic healing potential is limited. These challenges have motivated the development of model systems to study the factors that regulate tendon formation and tendon injury. Recent advances in understanding of embryonic and postnatal tendon formation have inspired approaches that aimed to mimic key aspects of tendon development. Model systems have also been developed to explore factors that regulate tendon injury and healing. We highlight current model systems that explore developmentally inspired cellular, mechanical, and biochemical factors in tendon formation and tenogenic stem cell differentiation. Next, we discuss in vivo, in vitro, ex vivo, and computational models of tendon injury that examine how mechanical loading and biochemical factors contribute to tendon pathologies and healing. These tendon development and injury models show promise for identifying the factors guiding tendon formation and tendon pathologies, and will ultimately improve regenerative tissue engineering strategies and clinical outcomes.

Glycine Supplementation – A Novel Therapeutic Strategy for Congenital Sideroblastic Anemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2087-2087
Author(s):  
Jason N Berman ◽  
Pedro Fernandez-Murray ◽  
Gheyath Nasrallah ◽  
Noelia Dufay ◽  
Conrad V Fernandez ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Aminolevulinic Acid ◽  
Protein Product ◽  
Microcytic Anemia ◽  
Model Systems ◽  
Transcription Activator ◽  
Zebrafish Model ◽  
Heme Synthesis ◽  
Beta Galactosidase

Abstract Abstract 2087 Congenital sideroblastic anemias (CSA) are inherited diseases, characterized by ineffective haematopoiesis, typically severe microcytic anemia and bone marrow sideroblasts representing excess iron deposition in the mitochondria of the erythroid precursors. More than 40% of CSA cases are attributed to mutations in the X-linked gene ALAS2. ALAS2 encodes the mitochondrial enzyme aminolevulinic acid synthase-2, which utilizes glycine to form 5-aminolevulinic acid (5-ALA), a crucial precursor in heme synthesis. Another gene, SLC25A38, has recently been implicated in the abnormal heme development noted in CSA. The function of the SLC25A38 protein product is uncertain, although it is thought to be an erythroid specific mitochondrial carrier family protein, transporting glycine across mitochondrial membranes. We employed yeast and zebrafish model systems in parallel to evaluate the absence of SLC25A38 or ALAS2 on heme synthesis in vivo and identify potential therapeutic strategies. HEM1 (ALAS2 homologue) mutant yeast were completely unable to make heme, whereas heme synthesis was significantly reduced in YDL119c (SLC25A38 homologue) mutant yeast. To monitor heme synthesis, we utilized a beta-galactosidase reporter linked to Pcyc1, which is only active following binding of the yeast Hap1 transcription activator in the presence of heme. Both HEM1 and YDL119c mutant yeast showed no beta-galactosidase activity, however activity in the YDL119c mutant was returned to 30% with the addition of 5-ALA and to 40% following treatment with glycine. Microarray studies of untreated and glycine treated YDL119c mutant yeast revealed increased expression of genes required to synthesize vitamin B6, a cofactor for the Hem1 enzyme in yeast and humans. Morpholino (MO)-mediated knockdown of the zebrafish homologues of SLC25A38 (slc25a38a and slc25a38b) or alas2 correlated with decreased hemoglobin levels by o-dianisidine staining and increased embryonic malformation and mortality. 5-ALA treatment either by addition to the egg water or by injection into the yolk failed to restore hemoglobinization in alas2 morphant embryos. By contrast, the addition of glycine to the egg water resulted in upregulation of hemoglobin to near normal levels in the majority of slc25a38a/b double morphant embryos. Our study demonstrates conserved heme synthesis pathways through evolution across species and further supports the contention that SLC25A38 functions as a glycine transporter. Most significantly, glycine supplementation emerged as an effective therapeutic strategy to restore heme synthesis in CSA caused by SLC25A38 deficiency, providing the rationale to support use of glycine in a clinical trial that is under development for these patients. Disclosures: McMaster: DeNovaMed: Equity Ownership.

scholarly journals An orthotopic glioblastoma animal model suitable for high-throughput screenings

2018 ◽  
Vol 20 (11) ◽  
pp. 1475-1484 ◽  
Author(s):  
Linda Pudelko ◽  
Steven Edwards ◽  
Mirela Balan ◽  
Daniel Nyqvist ◽  
Jonathan Al-Saadi ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Large Scale ◽  
Light Sheet ◽  
Time Lapse ◽  
Zebrafish Model ◽  
Light Sheet Microscopy ◽  
Disease Biology ◽  
Vertebrate Model

Abstract Background Glioblastoma (GBM) is an aggressive form of brain cancer with poor prognosis. Although murine animal models have given valuable insights into the GBM disease biology, they cannot be used in high-throughput screens to identify and profile novel therapies. The only vertebrate model suitable for large-scale screens, the zebrafish, has proven to faithfully recapitulate biology and pathology of human malignancies, and clinically relevant orthotopic zebrafish models have been developed. However, currently available GBM orthotopic zebrafish models do not support high-throughput drug discovery screens. Methods We transplanted both GBM cell lines as well as patient-derived material into zebrafish blastulas. We followed the behavior of the transplants with time-lapse microscopy and real-time in vivo light-sheet microscopy. Results We found that GBM material transplanted into zebrafish blastomeres robustly migrated into the developing nervous system, establishing an orthotopic intracranial tumor already 24 hours after transplantation. Detailed analysis revealed that our model faithfully recapitulates the human disease. Conclusion We have developed a robust, fast, and automatable transplantation assay to establish orthotopic GBM tumors in zebrafish. In contrast to currently available orthotopic zebrafish models, our approach does not require technically challenging intracranial transplantation of single embryos. Our improved zebrafish model enables transplantation of thousands of embryos per hour, thus providing an orthotopic vertebrate GBM model for direct application in drug discovery screens.

scholarly journals Deciphering the role of hydrophobic and hydrophilic bile acids in angiogenesis using in vitro and in vivo model systems

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2248-2257 ◽  
Author(s):  
Somanath Kundu ◽  
Sandhya Bansal ◽  
Kalai Mangai Muthukumarasamy ◽  
Chetana Sachidanandan ◽  
Rajender K. Motiani ◽  
...  
Keyword(s):  
Bile Acids ◽  
Chenodeoxycholic Acid ◽  
Model Systems ◽  
In Vivo Model ◽  
Zebrafish Model ◽  
Sar Studies

SAR studies revealed the pro-angiogenic properties of chenodeoxycholic acid in a zebrafish model.

scholarly journals CRISPR-NSID: anin vivoCRISPR/Cas9 negative selection screen reveals EZH2 as a druggable dependency factor in a genetic desmoid tumor model

2019 ◽  
Author(s):  
Thomas Naert ◽  
Tom Van Nieuwenhuysen ◽  
Suzan Demuynck ◽  
Sven de Grande ◽  
Joanna Przybyl ◽  
...  
Keyword(s):  
Negative Selection ◽  
Unmet Need ◽  
Tumor Model ◽  
Rapid Identification ◽  
Genetically Engineered ◽  
Model Systems ◽  
Desmoid Tumors ◽  
Cancer Models

AbstractIdentification of true dependencies in cancer is pivotal to the elucidation of novel therapeutic strategies to increase prospects for cancer patients. Unfortunately,in vivoidentification of genetic dependencies has long relied on expensive and time-consuming breeding of genetically engineered animal models. Recently,in vitroCRISPR/Cas9 screens provided a new method for rapid and genome-wide identification of genetic dependencies. Nevertheless, genetic dependencies would ideally be identified usingin vivocancer models initiated by clinically relevant oncogenic driver or tumor suppressor insults. Here, we report a new methodology calledCRISPR/Cas9-mediatedNegativeSelectionIdentification of geneticDependencies (CRISPR-NSID) that allowsin vivoelucidation of cancer cell vulnerabilities in genetic cancer models. The methodology hinges on the fact that for a genetic dependency there is an incapability for recovering tumors carrying biallelic frameshift mutations in this gene. We demonstrate how integrating experimentally determined, orin silicopredicted, probabilities of frameshift editing for any given gRNA can be employed to ascertain negative selection pressure on inactivation of a genetic dependency during tumorigenesis. As a proof-of-principle, we use CRISPR-NSID to identifyezh2andcreb3l1as genetic dependencies in desmoid tumors (desmoid-type fibromatosis) occurring in aXenopus tropicaliscancer model driven byapcmutations. Bridging CRISPR-NSID to a clinically unmet need, we further demonstrate the promise for EZH2 inhibition as a new therapeutic strategy for desmoid tumors. This study establishes a new methodology for rapid identification of genetic dependencies in monoclonal disorders with wide adaptability to other model systems and organisms.

scholarly journals The Lysine Methylase SMYD3 Modulates Mesendodermal Commitment during Development

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1233
Author(s):  
Raffaella Fittipaldi ◽  
Pamela Floris ◽  
Valentina Proserpio ◽  
Franco Cotelli ◽  
Monica Beltrame ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Model Systems ◽  
Embryonic Stem Cell Differentiation ◽  
In Vitro Differentiation ◽  
Cancer Models ◽  
Lineage Markers

SMYD3 (SET and MYND domain containing protein 3) is a methylase over-expressed in cancer cells and involved in oncogenesis. While several studies uncovered key functions for SMYD3 in cancer models, the SMYD3 role in physiological conditions has not been fully elucidated yet. Here, we dissect the role of SMYD3 at early stages of development, employing mouse embryonic stem cells (ESCs) and zebrafish as model systems. We report that SMYD3 depletion promotes the induction of the mesodermal pattern during in vitro differentiation of ESCs and is linked to an upregulation of cardiovascular lineage markers at later stages. In vivo, smyd3 knockdown in zebrafish favors the upregulation of mesendodermal markers during zebrafish gastrulation. Overall, our study reveals that SMYD3 modulates levels of mesendodermal markers, both in development and in embryonic stem cell differentiation.

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