Publications by authors named "Lawrence Schook"

96 Publications

Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity.

Geroscience 2021 Oct 15;43(5):2467-2483. Epub 2021 Sep 15.

Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA, USA.

DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n = 238 porcine tissues including blood, bladder, frontal cortex, kidney, liver, and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). Samples used in this study originated from Large White X Landrace crossbred pigs, Large White X Minnesota minipig crossbred pigs, and Wisconsin Miniature Swine™. We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, and GPR61) implicated by genetic studies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig's increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, breed-specific differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11357-021-00439-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599541PMC
October 2021

Swine models for translational oncological research: an evolving landscape and regulatory considerations.

Mamm Genome 2021 Sep 2. Epub 2021 Sep 2.

Department of Animal Science, Iowa State University, 2255 Kildee Hall, 806 Stange Road, Ames, IA, 50011, USA.

Swine biomedical models have been gaining in popularity over the last decade, particularly for applications in oncology research. Swine models for cancer research include pigs that have severe combined immunodeficiency for xenotransplantation studies, genetically modified swine models which are capable of developing tumors in vivo, as well as normal immunocompetent pigs. In recent years, there has been a low success rate for the approval of new oncological therapeutics in clinical trials. The two leading reasons for these failures are either due to toxicity and safety issues or lack of efficacy. As all therapeutics must be tested within animal models prior to clinical testing, there are opportunities to expand the ability to assess efficacy and toxicity profiles within the preclinical testing phases of new therapeutics. Most preclinical in vivo testing is performed in mice, canines, and non-human primates. However, swine models are an alternative large animal model for cancer research with similarity to human size, genetics, and physiology. Additionally, tumorigenesis pathways are similar between human and pigs in that similar driver mutations are required for transformation. Due to their larger size, the development of orthotopic tumors is easier than in smaller rodent models; additionally, porcine models can be harnessed for testing of new interventional devices and radiological/surgical approaches as well. Taken together, swine are a feasible option for preclinical therapeutic and device testing. The goals of this resource are to provide a broad overview on regulatory processes required for new therapeutics and devices for use in the clinic, cross-species differences in oncological therapeutic responses, as well as to provide an overview of swine oncology models that have been developed that could be used for preclinical testing to fulfill regulatory requirements.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00335-021-09907-yDOI Listing
September 2021

Perspective: Humanized Pig Models of Bladder Cancer.

Front Mol Biosci 2021 17;8:681044. Epub 2021 May 17.

Postgraduate Program in Biotechnology, Cancer Biotechnology Laboratory, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil.

Bladder cancer (BC) is the 10th most common neoplasia worldwide and holds expensive treatment costs due to its high recurrence rates, resistance to therapy and the need for lifelong surveillance. Thus, it is necessary to improve the current therapy options and identify more effective treatments for BC. Biological models capable of recapitulating the characteristics of human BC pathology are essential in evaluating the effectiveness of new therapies. Currently, the most commonly used BC models are experimentally induced murine models and spontaneous canine models, which are either insufficient due to their small size and inability to translate results to clinical basis (murine models) or rarely spontaneously observed BC (canine models). Pigs represent a potentially useful animal for the development of personalized tumors due to their size, anatomy, physiology, metabolism, immunity, and genetics similar to humans and the ability to experimentally induce tumors. Pigs have emerged as suitable biomedical models for several human diseases. In this sense, the present perspective focuses on the genetic basis for BC; presents current BC animal models available along with their limitations; and proposes the pig as an adequate animal to develop humanized large animal models of BC. Genetic alterations commonly found in human BC can be explored to create genetically defined porcine models, including the BC driver mutations observed in the FGFR3, PIK3CA, PTEN, RB1, HRAS, and TP53 genes. The development of such robust models for BC has great value in the study of pathology and the screening of new therapeutic and diagnostic approaches to the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2021.681044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165235PMC
May 2021

Transcriptional Profiling of Porcine HCC Xenografts Provides Insights Into Tumor Cell Microenvironment Signaling.

Front Genet 2021 29;12:657330. Epub 2021 Apr 29.

Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, representing the most common form of liver cancer. As HCC incidence and mortality continue to increase, there is a growing need for improved translational animal models to bridge the gap between basic HCC research and clinical practice to improve early detection and treatment strategies for this deadly disease. Recently the Oncopig cancer model-a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of and driver mutations-has been validated as a large animal translational model for human HCC. Due to the similar size, anatomy, physiology, immunology, genetics, and epigenetics between pigs and humans, the Oncopig has the potential to improve translation of novel diagnostic and therapeutic modalities into clinical practice. Recent studies have demonstrated the importance of tumor cells in shaping its surrounding microenvironment into one that is more proliferative, invasive, and metastatic; however, little is known about the impact of microenvironment signaling on HCC tumor biology and differential gene expression between HCC tumors and its tumor microenvironment (TME). In this study, transcriptional profiling was performed on Oncopig HCC xenograft tumors ( = 3) produced via subcutaneous injection of Oncopig HCC cells into severe combined immunodeficiency (SCID) mice. To differentiate between gene expression in the tumor and surrounding tumor microenvironment, RNA-seq reads originating from porcine (HCC tumor) and murine (microenvironment) cells were bioinformatically separated using Xenome. Principle component analysis (PCA) demonstrated clustering by group based on the expression of orthologous genes. Genes contributing to each principal component were extracted and subjected to functional analysis to identify alterations in pathway signaling between HCC cells and the microenvironment. Altered expression of genes associated with hepatic fibrosis deposition, immune response, and neo angiogenesis were observed. The results of this study provide insights into the interplay between HCC and microenvironment signaling , improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2021.657330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118521PMC
April 2021

Transarterial Embolization of Liver Cancer in a Transgenic Pig Model.

J Vasc Interv Radiol 2021 04 23;32(4):510-517.e3. Epub 2021 Jan 23.

Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Electronic address:

Purpose: To develop and characterize a porcine model of liver cancer that could be used to test new locoregional therapies.

Materials And Methods: Liver tumors were induced in 18 Oncopigs (transgenic pigs with Cre-inducible TP53 and KRAS mutations) by using an adenoviral vector encoding the Cre-recombinase gene. The resulting 60 tumors were characterized on multiphase contrast-enhanced CT, angiography, perfusion, micro-CT, and necropsy. Transarterial embolization was performed using 40-120 μm (4 pigs) or 100-300 μm (4 pigs) Embosphere microspheres. Response to embolization was evaluated on imaging. Complications were determined based on daily clinical evaluation, laboratory results, imaging, and necropsy.

Results: Liver tumors developed at 60/70 (86%) inoculated sites. Mean tumor size was 2.1 cm (range, 0.3-4 cm) at 1 week. Microscopically, all animals developed poorly differentiated to undifferentiated carcinomas accompanied by a major inflammatory component, which resembled undifferentiated carcinomas of the human pancreatobiliary tract. Cytokeratin and vimentin expression confirmed epithelioid and mesenchymal differentiation, respectively. Lymph node, lung, and peritoneal metastases were seen in some cases. On multiphase CT, all tumors had a hypovascular center, and 17/60 (28%) had a hypervascular rim. After transarterial embolization, noncontrast CT showed retained contrast medium in the tumors. Follow-up contrast-enhanced scan showed reduced size of tumors after embolization using either 40-120 μm or 100-300 μm Embosphere microspheres, while untreated tumors showed continued growth.

Conclusions: Liver tumors can be induced in a transgenic pig and can be successfully treated using bland embolization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvir.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451249PMC
April 2021

Transcriptional regulation of alcohol induced liver fibrosis in a translational porcine hepatocellular carcinoma model.

Biochimie 2021 Mar 12;182:73-84. Epub 2021 Jan 12.

Department of Radiology, University of Illinois at Chicago, United States; National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign, United States; Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, United States. Electronic address:

Hepatocellular carcinoma (HCC) is the 5th most common and 2nd deadliest cancer worldwide. HCC risk factors include alcohol induced liver cirrhosis, which prompts hepatic inflammation, cell necrosis, and fibrosis deposition. As 25% of HCC cases are associated with alcohol induced liver disease, understanding the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic responses are critical. This study utilized the Oncopig Cancer Model-a transgenic pig model that recapitulates human HCC through induced expression of KRAS and TP53 driver mutations-to investigate the molecular mechanisms underlying alcohol induced liver disease. Oncopigs (n = 5) underwent fibrosis induction via infusion of ethanol and ethiodized oil (1:3 v/v dosed at 0.75 mL/kg) into the hepatic arterial circulation. Eight-weeks post induction, liver tissue samples from fibrotic and age-matched control (n = 5) Oncopigs were collected for histological evaluation and transcriptional profiling. Increased hepatic inflammation and fibrosis was observed in fibrotic Oncopigs via pathological assessment. Transcriptional profiling (RNA-seq) resulted in the identification of 4387 differentially expressed genes between Oncopig fibrotic and control livers. GO term enrichment analysis identified pathway alterations associated with cirrhosis progression in humans, including cell proliferation, angiogenesis, extracellular matrix deposition, and oxidation-reduction. Key alterations include activation of hepatic stellate cells, increased matrix metalloproteinase production, and altered expression of ABC and SLC transporter genes involved in transport of anticancer drugs.These results demonstrate Oncopig liver fibrosis recapitulates transcriptional hallmarks of human cirrhosis, making the Oncopig an ideal model for studying the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356245PMC
March 2021

Generation of genetically tailored porcine liver cancer cells by CRISPR/Cas9 editing.

Biotechniques 2021 01 23;70(1):37-48. Epub 2020 Nov 23.

Department of Radiology, University of Illinois at Chicago, Chicago, IL 60612, USA.

Pigs provide a valuable large animal model for several diseases due to their similarity with humans in anatomy, physiology, genetics and drug metabolism. We recently generated a porcine model for and driven hepatocellular carcinoma (HCC) by autologous liver implantation. Here we describe a streamlined approach for developing genetically tailored porcine HCC cells by CRISPR/Cas9 gene editing and isolation of homogenous genetically validated cell clones. The combination of CRISPR/Cas9 editing of HCC cells described herein with the orthotopic HCC model enables development of various porcine HCC models, each with a specific mutational profile. This allows modeling the effect of different driver mutation combinations on tumor progression and testing of novel targeted therapeutic approaches in a clinically relevant large animal model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2144/btn-2020-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852845PMC
January 2021

Electrothermal soft manipulator enabling safe transport and handling of thin cell/tissue sheets and bioelectronic devices.

Sci Adv 2020 Oct 16;6(42). Epub 2020 Oct 16.

Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

"Living" cell sheets or bioelectronic chips have great potentials to improve the quality of diagnostics and therapies. However, handling these thin and delicate materials remains a grand challenge because the external force applied for gripping and releasing can easily deform or damage the materials. This study presents a soft manipulator that can manipulate and transport cell/tissue sheets and ultrathin wearable biosensing devices seamlessly by recapitulating how a cephalopod's suction cup works. The soft manipulator consists of an ultrafast thermo-responsive, microchanneled hydrogel layer with tissue-like softness and an electric heater layer. The electric current to the manipulator drives microchannels of the gel to shrink/expand and results in a pressure change through the microchannels. The manipulator can lift/detach an object within 10 s and can be used repeatedly over 50 times. This soft manipulator would be highly useful for safe and reliable assembly and implantation of therapeutic cell/tissue sheets and biosensing devices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abc5630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567602PMC
October 2020

Induction and characterization of pancreatic cancer in a transgenic pig model.

PLoS One 2020 21;15(9):e0239391. Epub 2020 Sep 21.

Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Background: Preclinical testing of new locoregional therapies for pancreatic cancer has been challenging, due to the lack of a suitable large animal model.

Purpose: To develop and characterize a porcine model of pancreatic cancer. Unlike small animals, pigs have similar physiology, drug dosing, and immune response to humans. Locoregional therapy in pigs can be performed using the same size catheters and devices as in humans.

Methods: The Oncopig is a transgenic pig with Cre-inducible TP53R167H and KRASG12D mutations. In 12 Oncopigs, CT-guided core biopsy of the pancreas was performed. The core biopsy was incubated with an adenoviral vector carrying the Cre recombinase gene. The transformed core biopsy was injected back into the pancreas (head, tail, or both). The resulting tumors (n = 19) were characterized on multi-phase contrast-enhanced CT, and on pathology, including immunohistochemistry. Angiographic characterization of the tumors was performed in 3 pigs.

Results: Pancreatic tumors developed at 19 out of 22 sites (86%) that were inoculated. Average tumor size was 3.0 cm at 1 week (range: 0.5-5.1 cm). H&E and immunohistochemical stains revealed undifferentiated carcinomas, similar to those of the pancreatobiliary system in humans. Neoplastic cells were accompanied by a major inflammatory component. 1 of 12 pigs only had inflammatory nodules without evidence of neoplasia. On multiphase CT, tumors were hypovascular compared to the normal pancreas. There was no pancreatic duct dilation. In 3 pigs, angiography was performed, and in all 3 cases, the artery supplying the pancreatic tumor could be catheterized using a 2.4 F microcatheter. Selective angiography showed the pancreatic tumor, without extra-pancreatic perfusion.

Conclusion: Pancreatic cancer can be induced in a transgenic pig. Intra-arterial procedures using catheters designed for human interventions were technically feasible in this large animal model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239391PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505440PMC
November 2020

Development and comprehensive characterization of porcine hepatocellular carcinoma for translational liver cancer investigation.

Oncotarget 2020 Jul 14;11(28):2686-2701. Epub 2020 Jul 14.

Department of Radiology, University of Illinois at Chicago, Chicago, IL, USA.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide. New animal models that faithfully recapitulate human HCC phenotypes are required to address unmet clinical needs and advance standard-of-care therapeutics. This study utilized the Oncopig Cancer Model to develop a translational porcine HCC model which can serve as a bridge between murine studies and human clinical practice. Reliable development of Oncopig HCC cell lines was demonstrated through hepatocyte isolation and Cre recombinase exposure across 15 Oncopigs. Oncopig and human HCC cell lines displayed similar cell cycle lengths, alpha-fetoprotein production, arginase-1 staining, chemosusceptibility, and drug metabolizing enzyme expression. The ability of Oncopig HCC cells to consistently produce tumors was confirmed via subcutaneous (SQ) injection into immunodeficient mice and Oncopigs. Reproducible development of intrahepatic tumors in an alcohol-induced fibrotic microenvironment was achieved via engraftment of SQ tumors into fibrotic Oncopig livers. Whole-genome sequencing demontrated intrahepatic tumor tissue resembled human HCC at the genomic level. Finally, Oncopig HCC cells are amenable to gene editing for development of personalized HCC tumors. This study provides a novel, clinically-relevant porcine HCC model which holds great promise for improving HCC outcomes through testing of novel therapeutic approaches to accelerate and enhance clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.27647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367657PMC
July 2020

An improved pig reference genome sequence to enable pig genetics and genomics research.

Gigascience 2020 06;9(6)

Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.

Background: The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model given its similarity in size, anatomy, physiology, metabolism, pathology, and pharmacology to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete, and unresolved redundancies, short-range order and orientation errors, and associated misassembled genes limited its utility.

Results: We present 2 annotated highly contiguous chromosome-level genome assemblies created with more recent long-read technologies and a whole-genome shotgun strategy, 1 for the same Duroc female (Sscrofa11.1) and 1 for an outbred, composite-breed male (USMARCv1.0). Both assemblies are of substantially higher (>90-fold) continuity and accuracy than Sscrofa10.2.

Conclusions: These highly contiguous assemblies plus annotation of a further 11 short-read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gigascience/giaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448572PMC
June 2020

Porcine cancer models: potential tools to enhance cancer drug trials.

Expert Opin Drug Discov 2020 08 7;15(8):893-902. Epub 2020 May 7.

Department of Radiology, University of Illinois at Chicago , Chicago, IL, USA.

Introduction: The amount of time and money invested into cancer drug research, development, and clinical trials has continually increased over the past few decades. Despite record high cancer drug approval rates, cancer remains a leading cause of death. This suggests the need for more effective tools to help bring novel therapies to clinical practice in a timely manner.

Areas Covered: In this review, current issues associated with clinical trials are discussed, specifically focusing on poor accrual rates and time for trial completion. In addition, details regarding preclinical studies required before advancing to clinical trials are discussed, including advantages and limitations of current preclinical animal cancer models and their relevance to human cancer trials. Finally, new translational porcine cancer models (Oncopig Cancer Model (OCM)) are presented as potential co-clinical trial models.

Expert Opinion: In order to address issues impacting the poor success rate of oncology clinical trials, we propose the incorporation of the transformative OCM 'co-clinical trial' pathway into the cancer drug approval process. Due to the Oncopig's high homology to humans and similar tumor phenotypes, their utilization can provide improved preclinical prediction of both drug safety and efficacy prior to investing significant time and money in human clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17460441.2020.1757644DOI Listing
August 2020

Altered Hippocampal Epigenetic Regulation Underlying Reduced Cognitive Development in Response to Early Life Environmental Insults.

Genes (Basel) 2020 02 4;11(2). Epub 2020 Feb 4.

Department of Radiology, University of Illinois at Chicago, Chicago, IL 60607, USA.

The hippocampus is involved in learning and memory and undergoes significant growth and maturation during the neonatal period. Environmental insults during this developmental timeframe can have lasting effects on brain structure and function. This study assessed hippocampal DNA methylation and gene transcription from two independent studies reporting reduced cognitive development stemming from early life environmental insults (iron deficiency and porcine reproductive and respiratory syndrome virus (PRRSv) infection) using porcine biomedical models. In total, 420 differentially expressed genes (DEGs) were identified between the reduced cognition and control groups, including genes involved in neurodevelopment and function. Gene ontology (GO) terms enriched for DEGs were associated with immune responses, angiogenesis, and cellular development. In addition, 116 differentially methylated regions (DMRs) were identified, which overlapped 125 genes. While no GO terms were enriched for genes overlapping DMRs, many of these genes are known to be involved in neurodevelopment and function, angiogenesis, and immunity. The observed altered methylation and expression of genes involved in neurological function suggest reduced cognition in response to early life environmental insults is due to altered cholinergic signaling and calcium regulation. Finally, two DMRs overlapped with two DEGs, and , which are associated with blood brain barrier permeability and regulatory T-cell activation, respectively. These results support the role of altered hippocampal DNA methylation and gene expression in early life environmentally-induced reductions in cognitive development across independent studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11020162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074491PMC
February 2020

Catalytic microgelators for decoupled control of gelation rate and rigidity of the biological gels.

J Control Release 2020 01 11;317:166-180. Epub 2019 Nov 11.

Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA. Electronic address:

Fibrin gels have been extensively used for three-dimensional cell culture, bleeding control, and molecular and cell therapies because the fibrous networks facilitate biomolecular and cell transport. However, a small window for gelation makes it difficult to handle the gels for desired preparation and transport. Several methods developed to control gelation rates often alter the microstructure, thereby affecting the mechanical response. We hypothesized that a particle designed to discharge thrombin cargos in response to an external stimulus, such as HO, would provide control of the gelation rate over a broad range while strengthening the gel. We examined this hypothesis by assembling poly (lactic-co-glycolic acid) (PLGA) particles loaded with thrombin and MnO nanosheets that decompose HO to O gas. The resulting particles named as catalytic microgelator were mixed with fibrinogen solution or blood containing 0.2mM HO. Due to the increased internal pressure, these particles released a 3-fold larger mass of thrombin than PLGA particles loaded only with thrombin. As a consequence, catalytic microgelators increased the gelation time by one order of magnitude and the elastic modulus by a factor of two compared with the fibrin gel formed by directly mixing fibrinogen and thrombin in solution. These catalytic microgelators also served to clot blood, unlike PLGA particles loaded with thrombin. The resulting blood clot was also more rigid than the blood clot formed by thrombin solution. The results of this study would serve as a new paradigm in controlling gelation kinetics of pre-gel solution and mechanical properties of the post-gel matrix.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.10.029DOI Listing
January 2020

Editorial: "Humanized" Large Animal Cancer Models: Accelerating Time and Effectiveness of Clinical Trials.

Front Oncol 2019 27;9:793. Epub 2019 Aug 27.

Biomedical and Genomic Research Group, Department of Animal Sciences, University of Wisconsin-Madison, Madison, WI, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718447PMC
August 2019

TM4SF18 is aberrantly expressed in pancreatic cancer and regulates cell growth.

PLoS One 2019 21;14(3):e0211711. Epub 2019 Mar 21.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois, Chicago, Illinois, United States of America.

Current therapies for pancreatic ductal adenocarcinoma (PDAC) only modestly impact survival and can be highly toxic. A greater understanding of the molecules regulating this disease is critical for identifying new drug targets and developing more effective therapies. The L6 family of proteins are known to be positive regulators of tumor growth and metastasis among various cancers. However, little is known about the L6 family member TM4SF18. We investigated the expression and localization of the TM4SF18 protein in normal human pancreas and in PDAC tissue. Utilizing immunohistochemistry (IHC) and western blot analysis, our studies for the first time demonstrate that TM4SF18 is highly expressed in PDAC tumor epithelium. Furthermore, we identified TM4SF18 to be expressed in normal acinar tissue and weakly expressed in normal ducts. Although there is minimal expression in normal ducts, we observed increased TM4SF18 levels in preneoplastic ducts and tumor epithelium. To investigate a functional role of TM4SF18 in PDAC we developed stably-expressing inducible shRNA pancreatic cancer cell lines. Knockdown of the TM4SF18 protein led to a significant decrease in Capan-1 cell growth as measured by the MTT assay, demonstrating this molecule to be a novel regulator of PDAC. Uniquely there is no ortholog of the TM4SF18 gene in mouse or rat prompting us to seek other in vivo experimental models. Using IHC and western blot analysis, expression of TM4SF18 was confirmed in the porcine PDAC model, thus we establish an alternative model to investigate this gene. TM4SF18 represents a promising novel biomarker and therapeutic target for pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428261PMC
December 2019

Translating Human Cancer Sequences Into Personalized Porcine Cancer Models.

Front Oncol 2019 25;9:105. Epub 2019 Feb 25.

Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States.

The global incidence of cancer is rapidly rising, and despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. Cancer is caused by the accumulation of a series of gene mutations called driver mutations that confer selective growth advantages to tumor cells. As cancer therapies move toward personalized medicine, predictive modeling of the role driver mutations play in tumorigenesis and therapeutic susceptibility will become essential. The development of next-generation sequencing technology has made the evaluation of mutated genes possible in clinical practice, allowing for identification of driver mutations underlying cancer development in individual patients. This, combined with recent advances in gene editing technologies such as CRISPR-Cas9 enables development of personalized tumor models for prediction of treatment responses for mutational profiles observed clinically. Pigs represent an ideal animal model for development of personalized tumor models due to their similar size, anatomy, physiology, metabolism, immunity, and genetics compared to humans. Such models would support new initiatives in precision medicine, provide approaches to create disease site tumor models with designated spatial and temporal clinical outcomes, and create standardized tumor models analogous to human tumors to enable therapeutic studies. In this review, we discuss the process of utilizing genomic sequencing approaches, gene editing technologies, and transgenic porcine cancer models to develop clinically relevant, personalized large animal cancer models for use in co-clinical trials, ultimately improving treatment stratification and translation of novel therapeutic approaches to clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2019.00105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401626PMC
February 2019

Of Mice, Dogs, Pigs, and Men: Choosing the Appropriate Model for Immuno-Oncology Research.

ILAR J 2018 12;59(3):247-262

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kgs. Lyngby, Denmark.

The immune system plays dual roles in response to cancer. The host immune system protects against tumor formation via immunosurveillance; however, recognition of the tumor by immune cells also induces sculpting mechanisms leading to a Darwinian selection of tumor cell variants with reduced immunogenicity. Cancer immunoediting is the concept used to describe the complex interplay between tumor cells and the immune system. This concept, commonly referred to as the three E's, is encompassed by 3 distinct phases of elimination, equilibrium, and escape. Despite impressive results in the clinic, cancer immunotherapy still has room for improvement as many patients remain unresponsive to therapy. Moreover, many of the preclinical results obtained in the widely used mouse models of cancer are lost in translation to human patients. To improve the success rate of immuno-oncology research and preclinical testing of immune-based anticancer therapies, using alternative animal models more closely related to humans is a promising approach. Here, we describe 2 of the major alternative model systems: canine (spontaneous) and porcine (experimental) cancer models. Although dogs display a high rate of spontaneous tumor formation, an increased number of genetically modified porcine models exist. We suggest that the optimal immuno-oncology model may depend on the stage of cancer immunoediting in question. In particular, the spontaneous canine tumor models provide a unique platform for evaluating therapies aimed at the escape phase of cancer, while genetically engineered swine allow for elucidation of tumor-immune cell interactions especially during the phases of elimination and equilibrium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ilar/ily014DOI Listing
December 2018

Design, Synthesis, and Characterization of Globular Orphan Nuclear Receptor Regulator with Biological Activity in Soft Tissue Sarcoma.

J Med Chem 2018 12 14;61(23):10739-10752. Epub 2018 Nov 14.

Department of Bioengineering , University of Illinois at Urbana-Champaign , Urbana , Illinois 61801 , United States.

Sarcomas are rare and heterogeneous cancer variants of mesenchymal origin. Their genetic heterogeneity coupled with uncertain histogenesis makes them difficult to treat and results in poor prognosis. In this work, we show that structure-based drug discovery involving computational modeling can be used to identify a new retinoid X receptor (RXR) agonist ligand with a bis(indolyl)methane scaffold. This agent co-self-assembles with an amphiphilic diblock copolymer resulting in nanoparticles (Nano-RXR) with excellent kinetic stability, which were evaluated for efficacy and safety in transformed sarcoma cells, 63-3 Cre and 141-10 Cre of pig origin, and in rodent xenograft models. Responses at gene and protein levels established the treatment approach as a highly effective RXR agonist across cell, rodent, and "Oncopig" models. Interestingly, Nano-RXR was not only able to modulate metabolic and transporter genes related to orphan nuclear receptors but also played a major role in modulating programmed cell death in sarcomas developed in Oncopigs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b01387DOI Listing
December 2018

Editorial: Building Strategies for Porcine Cancer Models.

Front Genet 2018 2;9:377. Epub 2018 Oct 2.

Animal Science, University of Illinois at Urbana-Champaign, Champaign, IL, United States.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2018.00377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176655PMC
October 2018

KRAS and TP53 Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs.

Sci Rep 2018 08 22;8(1):12548. Epub 2018 Aug 22.

University of Illinois Department of Animal Sciences, Urbana-Champaign, IL, USA.

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRAS-TP53 cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreatic duct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-30916-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105629PMC
August 2018

Genetically Induced Tumors in the Oncopig Model Invoke an Antitumor Immune Response Dominated by Cytotoxic CD8β T Cells and Differentiated γδ T Cells Alongside a Regulatory Response Mediated by FOXP3 T Cells and Immunoregulatory Molecules.

Front Immunol 2018 7;9:1301. Epub 2018 Jun 7.

Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.

In recent years, immunotherapy has shown considerable promise in the management of several malignancies. However, the majority of preclinical studies have been conducted in rodents, the results of which often translate poorly to patients given the substantial differences between murine and human immunology. As the porcine immune system is far more analogous to that of humans, pigs may serve as a supplementary preclinical model for future testing of such therapies. We have generated the genetically modified Oncopig with inducible tumor formation resulting from concomitant and mutations under control of an adenoviral vector Cre-recombinase (AdCre). The objective of this study was to characterize the tumor microenvironment in this novel animal model with respect to T-cell responses in particular and to elucidate the potential use of Oncopigs for future preclinical testing of cancer immunotherapies. In this study, we observed pronounced intratumoral T-cell infiltration with a strong CD8β predominance alongside a representation of highly differentiated γδ T cells. The infiltrating CD8β T cells displayed increased expression of the cytotoxic marker perforin when compared with the peripheral T-cell pool. Similarly, there was robust granzyme B staining localizing to the tumors; affirming the presence of cytotoxic immune cells within the tumor. In parallel with this antitumor immune response, the tumors displayed enrichment in FOXP3-expressing T cells and increased gene expression of indoleamine 2,3-dioxygenase 1 (), cytotoxic T-lymphocyte-associated protein 4 (), and programmed death-ligand 1 (). Finally, we investigated the Oncopig immune system in mediating antitumor immunity. We observed pronounced killing of autologous tumor cells, which demonstrates the propensity of the Oncopig immune system to recognize and mount a cytotoxic response against tumor cells. Together, these findings suggest innate and adaptive recognition of the induced tumors with a concomitant suppression of T-cell effector functions. Combined, the data support that the Oncopig may serve as a valuable model for future preclinical testing of immunotherapies aimed at reactivating tumor-directed cytotoxicity .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.01301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999797PMC
August 2019

Characterization of an Inducible Alcoholic Liver Fibrosis Model for Hepatocellular Carcinoma Investigation in a Transgenic Porcine Tumorigenic Platform.

J Vasc Interv Radiol 2018 08 7;29(8):1194-1202.e1. Epub 2018 Jun 7.

Department of Radiology, University of Illinois Health, 1740 West Taylor Street, MC 931, Chicago, Illinois, 60612. Electronic address:

Purpose: This study used the Oncopig Cancer Model (OCM) to develop alcohol-induced fibrosis in a porcine model capable of developing hepatocellular carcinoma.

Materials And Methods: Liver injury was induced in 8-week-old Oncopigs (n = 10) via hepatic transarterial infusion of 0.75 mL/kg ethanol-ethiodized oil (1:3 v/v). Feasibility was assessed in an initial Oncopig cohort (n = 5) by histologic analysis at 8 weeks after induction, and METAVIR results were compared to age- and sex-matched healthy controls (n = 5). Liver injury was then induced in a second OCM cohort (n = 5) for a time-course study, with post-induction disease surveillance via biweekly physical exam, lab analysis, and liver biopsies until 20 weeks after induction.

Results: In Cohort 1, 8-week post-induction liver histologic analysis revealed median METAVIR F3 (range, F3-F4) fibrosis, A2 (range, A2-A3) inflammation, and 15.3% (range, 5.0%-22.9%) fibrosis. METAVIR and inflammation scores were generally elevated compared to healthy controls (F0-F1, P = 0.0013; A0-A1, P = .0013; median percent fibrosis 8.7%, range, 5.8%-12.1%, P = .064). In Cohort 2, histologic analysis revealed peak fibrosis severity of median METAVIR F3 (range, F2-F3). However, lack of persistent alcohol exposure resulted in liver recovery, with median METAVIR F2 (range, F1-F2) fibrosis at 20 weeks after induction. No behavioral or biochemical abnormalities were observed to indicate liver decompensation.

Conclusions: This study successfully validated a protocol to develop METAVIR F3-F4 fibrosis within 8 weeks in the OCM, supporting its potential to serve as a model for hepatocellular carcinoma in a fibrotic liver background. Further investigation is required to determine if repeated alcohol liver injury is required to develop an irreversible METAVIR grade F4 porcine cirrhosis model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jvir.2018.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388685PMC
August 2018

The Oncopig Cancer Model as a Complementary Tool for Phenotypic Drug Discovery.

Front Pharmacol 2017 5;8:894. Epub 2017 Dec 5.

Biotechnology Graduate Program, Molecular and Cellular Oncology Research Group, Laboratory of Cancer Biotechnology, Technology Development Center, Federal University of Pelotas, Pelotas, Brazil.

The screening of potential therapeutic compounds using phenotypic drug discovery (PDD) is being embraced once again by researchers and pharmaceutical companies as an approach to enhance the development of new effective therapeutics. Before the genomics and molecular biology era and the consecutive emergence of targeted-drug discovery approaches, PDD was the most common platform used for drug discovery. PDD, also known as phenotypic screening, consists of screening potential compounds in either cellular or animal models to identify compounds resulting in a desirable phenotypic change. Using this approach, the biological targets of the compounds are not taken into consideration. Suitable animal models are crucial for the continued validation and discovery of new drugs, as compounds displaying promising results in phenotypic cell-based and small animal model screenings often fail in clinical trials. Indeed, this is mainly a result of differential anatomy, physiology, metabolism, immunology, and genetics between humans and currently used pre-clinical small animal models. In contrast, pigs are more predictive of therapeutic treatment outcomes in humans than rodents. In addition, pigs provide an ideal platform to study cancer due to their similarities with humans at the anatomical, physiological, metabolic, and genetic levels. Here we provide a mini-review on the reemergence of PDD in drug development, highlighting the potential of porcine cancer models for improving pre-clinical drug discovery and testing. We also present precision medicine based genetically defined swine cancer models developed to date and their potential as biomedical models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2017.00894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723300PMC
December 2017

A validated, transitional and translational porcine model of hepatocellular carcinoma.

Oncotarget 2017 Sep 29;8(38):63620-63634. Epub 2017 Jun 29.

Department of Animal Sciences, University of Illinois, Urbana, IL, USA.

Difficult questions are confronting clinicians attempting to improve hepatocellular carcinoma (HCC) outcomes. A large animal model with genetic, anatomical, and physiological similarities to humans is required to transition from mouse models to human clinical trials to address unmet clinical needs. To validate our previously reported inducible porcine cancer model (Oncopig) as a transitional HCC model, Oncopig hepatocyte cultures were transformed using Cre recombinase. The resulting porcine HCC cells (pHCC) expressed oncogenic and , and displayed nuclear pleomorphisms with pale to granular cytoplasm arranged in expanded plates similar to human HCC histopathology. Human HCC transcriptional hallmarks were detected in pHCC cells using RNA-seq, including reactivation, apoptosis evasion, angiogenesis activation, and Wnt signaling activation. Master regulators of gene expression were conserved across Oncopig and 18 human HCC cell lines. pHCC injection into SCID mice resulted in tumors recapitulating human HCC characteristics, including thick trabeculae formation, pseudoacini patterning, and sheets of well-vascularized stroma. Finally, autologous injection of pHCC cells subcutaneously yielded a tumor histologically characterized as Edmondson Steiner (HCC nuclear grade assessment system) grade 2 HCC with trabecular patterning and T-lymphocyte infiltration. These data demonstrate the Oncopig HCC model's utility for improving detection, treatment, and biomarker discovery relevant to human HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.18872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609948PMC
September 2017

Genome-wide SNP data unveils the globalization of domesticated pigs.

Genet Sel Evol 2017 Sep 21;49(1):71. Epub 2017 Sep 21.

Animal Breeding and Genomics, Wageningen University, Wageningen, The Netherlands.

Background: Pigs were domesticated independently in Eastern and Western Eurasia early during the agricultural revolution, and have since been transported and traded across the globe. Here, we present a worldwide survey on 60K genome-wide single nucleotide polymorphism (SNP) data for 2093 pigs, including 1839 domestic pigs representing 122 local and commercial breeds, 215 wild boars, and 39 out-group suids, from Asia, Europe, America, Oceania and Africa. The aim of this study was to infer global patterns in pig domestication and diversity related to demography, migration, and selection.

Results: A deep phylogeographic division reflects the dichotomy between early domestication centers. In the core Eastern and Western domestication regions, Chinese pigs show differentiation between breeds due to geographic isolation, whereas this is less pronounced in European pigs. The inferred European origin of pigs in the Americas, Africa, and Australia reflects European expansion during the sixteenth to nineteenth centuries. Human-mediated introgression, which is due, in particular, to importing Chinese pigs into the UK during the eighteenth and nineteenth centuries, played an important role in the formation of modern pig breeds. Inbreeding levels vary markedly between populations, from almost no runs of homozygosity (ROH) in a number of Asian wild boar populations, to up to 20% of the genome covered by ROH in a number of Southern European breeds. Commercial populations show moderate ROH statistics. For domesticated pigs and wild boars in Asia and Europe, we identified highly differentiated loci that include candidate genes related to muscle and body development, central nervous system, reproduction, and energy balance, which are putatively under artificial selection.

Conclusions: Key events related to domestication, dispersal, and mixing of pigs from different regions are reflected in the 60K SNP data, including the globalization that has recently become full circle since Chinese pig breeders in the past decades started selecting Western breeds to improve local Chinese pigs. Furthermore, signatures of ongoing and past selection, acting at different times and on different genetic backgrounds, enhance our insight in the mechanism of domestication and selection. The global diversity statistics presented here highlight concerns for maintaining agrodiversity, but also provide a necessary framework for directing genetic conservation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12711-017-0345-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609043PMC
September 2017

3D Printed Stem-Cell-Laden, Microchanneled Hydrogel Patch for the Enhanced Release of Cell-Secreting Factors and Treatment of Myocardial Infarctions.

ACS Biomater Sci Eng 2017 Sep 20;3(9):1980-1987. Epub 2016 Jul 20.

Department of Bioengineering, University of Illinois at Urbana-Champaign, 1270 Digital Computer Laboratory, MC-278, Urbana, Illinois 61801-2987, United States.

Over the past several years, biomaterials loaded with mesenchymal stem cells (MSCs) have increasingly been used to reduce the myocardial fate of postinfarction collagen deposition and scar tissue formation. Despite successful gains, therapeutic efficacy has remained limited because of restricted transport of cell-secreting factors at the site of implantation. We hypothesized that an MSC-laden hydrogel patch with multiple microchannels would retain transplanted cells on target tissue and support transport of cell-secreting factors into tissue. By doing so, the gel patch will improve the therapeutic potential of the cells and minimize the degradation of myocardial tissue postinfarction. To examine this hypothesis, a stereolithographic apparatus (SLA) was used to introduce microchannels of controlled diameters (e.g., 500 and 1000 μm) during in situ cross-linking reaction of poly(ethylene glycol)dimethacrylate solution suspended with cells. Placement of the MSC-laden, microchanneled gel patch on the occluded left coronary artery in a murine model showed significant improvement in the ejection fraction, fractional shortening, and stroke volume, compared with gel patches without MSCs and MSC-laden gel patches without microchannels. In particular, the microchannels significantly reduced the number of cells required to recover cardiac function, while minimizing cardiac remodeling. In sum, the microchanneled gel patch would provide a means to prevent abnormal fibrosis resulting from acute ischemic injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsbiomaterials.6b00176DOI Listing
September 2017

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform.

Front Oncol 2017 23;7:190. Epub 2017 Aug 23.

Department of Radiology, University of Illinois at Chicago, Chicago, IL, United States.

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model-the Oncopig Cancer Model (OCM)-as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, and , the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2017.00190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572387PMC
August 2017

Oncopig Soft-Tissue Sarcomas Recapitulate Key Transcriptional Features of Human Sarcomas.

Sci Rep 2017 06 1;7(1):2624. Epub 2017 Jun 1.

Department of Animal Sciences, University of Illinois, Urbana, Illinois, USA.

Human soft-tissue sarcomas (STS) are rare mesenchymal tumors with a 5-year survival rate of 50%, highlighting the need for further STS research. Research has been hampered by limited human sarcoma cell line availability and the large number of STS subtypes, making development of STS cell lines and animal models representative of the diverse human STS subtypes critical. Pigs represent ideal human disease models due to their similar size, anatomy, metabolism, and genetics compared to humans. The Oncopig encodes inducible KRAS and TP53 transgenes, allowing for STS modeling in a spatial and temporal manner. This study utilized Oncopig STS cell line (fibroblast) and tumor (leiomyosarcoma) RNA-seq data to compare Oncopig and human STS expression profiles. Altered expression of 3,360 and 7,652 genes was identified in Oncopig STS cell lines and leiomyosarcomas, respectively. Transcriptional hallmarks of human STS were observed in Oncopig STS, including altered TP53 signaling, Wnt signaling activation, and evidence of epigenetic reprogramming. Furthermore, master regulators of Oncopig STS expression were identified, including FOSL1, which was previously identified as a potential human STS therapeutic target. These results demonstrate the Oncopig STS model's ability to mimic human STS transcriptional profiles, providing a valuable resource for sarcoma research and cell line development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-02912-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453942PMC
June 2017
-->