Development of a genetically tailored implantation hepatocellular carcinoma model in Oncopigs by somatic cell CRISPR editing.

Hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis, necessitating preclinical models for evaluating novel therapies. Large-animal models are particularly valuable for assessing locoregional therapies, which are widely employed across HCC stages. This study aimed to develop a large-animal HCC model with tailored tumor mutations.

Translational Relevance and Future Integration of the Oncopig Cancer Model in Preclinical Applications.

Porcine cancer models offer a valuable platform for evaluating interventions such as devices, surgeries, and locoregional therapies, which are often challenging to test in mouse models. In addition to size and anatomical similarities with humans, pigs share greater similarities in genetics, immunity, drug metabolism, and metabolic rate with humans as compared to mouse models, increasing their translational relevance. This review focuses on the Oncopig Cancer Model, a genetically engineered porcine model designed to recapitulate human cancer.

Oncopig bladder cancer cells recapitulate human bladder cancer treatment responses .

Introduction: Bladder cancer is a common neoplasia of the urinary tract that holds the highest cost of lifelong treatment per patient, highlighting the need for a continuous search for new therapies for the disease. Current bladder cancer models are either imperfect in their ability to translate results to clinical practice (mouse models), or rare and not inducible (canine models). Swine models are an attractive alternative to model the disease due to their similarities with humans on several levels.

Hepatocellular Carcinoma Epigenetic Patterns Correspond to Differences in Ethnoracial Status and Treatment Response in a Single-Center Retrospective Study.

Purpose: To correlate epigenetic patterns with ethnoracial status and locoregional therapy (LRT) response in patients with hepatocellular carcinoma (HCC).

Materials And Methods: DNA and RNA were extracted from 47 distinct formalin-fixed paraffin-embedded tumor samples from 42 patients with HCC (n = 14 Black, n = 19 White, n = 9 Hispanic). LRT response was determined using computed tomography (CT) or magnetic resonance (MR) imaging 3 months posttreatment of 35 tumors (n = 22 complete response, n = 13 retreatment candidates).

Pigs as Clinically Relevant Models for Synergizing Interventional Oncology and Immunotherapy.

Traditionally, rodent cancer models have driven preclinical oncology research. However, they do not fully recapitulate characteristics of human cancers, and their size poses challenges when evaluating tools in the interventional oncologists' armamentarium. Pig models, however, have been the gold standard for validating surgical procedures.

Swine global genomic resources: insights into wild and domesticated populations.

Suids, both domesticated and wild, are found on all continents except for Antarctica and provide valuable food resources for humans in addition to serving as important models for biomedical research. Continuing advances in genome sequencing have allowed researchers to compare the genomes from diverse populations of suids helping to clarify their evolution and dispersal. Further analysis of these samples may provide clues to improve disease resistance/resilience and productivity in domestic suids as well as better ways of classifying and conserving genetic diversity within wild and captive suids.

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.

DNA methylation networks underlying mammalian traits.

Using DNA methylation profiles ( = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors.

Induction and preliminary characterization of neoplastic pulmonary nodules in a transgenic pig model.

Objectives: Lung cancer models in large animals are lacking. Oncopigs are transgenic pigs that carry both KRAS and TP53 Cre-inducible mutations. This study aimed to develop and histologically characterize a swine model of lung cancer that could serve for preclinical studies evaluating locoregional therapies.

The Oncopig as an Emerging Model to Investigate Copper Regulation in Cancer.

Emerging evidence points to several fundamental contributions that copper (Cu) has to promote the development of human pathologies such as cancer. These recent and increasing identification of the roles of Cu in cancer biology highlights a promising field in the development of novel strategies against cancer. Cu and its network of regulatory proteins are involved in many different contextual aspects of cancer from driving cell signaling, modulating cell cycle progression, establishing the epithelial-mesenchymal transition, and promoting tumor growth and metastasis.

Effect of CRISPR Knockout of or on Proliferation and Migration of Porcine Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive disease lacking effective treatment. Animal models of HCC are necessary for preclinical evaluation of the safety and efficacy of novel therapeutics. Large animal models of HCC allow testing image-guided locoregional therapies, which are widely used in the management of HCC.

Staging Liver Fibrosis by Fibroblast Activation Protein Inhibitor PET in a Human-Sized Swine Model.

Current methods of staging liver fibrosis have notable limitations. We investigated the utility of PET in staging liver fibrosis by correlating liver uptake of Ga-labeled fibroblast activation protein inhibitor (FAPI) with histology in a human-sized swine model. Five pigs underwent baseline Ga-FAPI-46 (Ga-FAPI) PET/MRI and liver biopsy, followed by liver parenchymal embolization, 8 wk of oral alcohol intake, endpoint Ga-FAPI PET/MRI, and necropsy.

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

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™.

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

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 molecular and cellular basis of copper dysregulation and its relationship with human pathologies.

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs.

Perspective: Humanized Pig Models of Bladder Cancer.

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.

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

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.

Transarterial Embolization of Liver Cancer in a Transgenic Pig Model.

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.

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

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.

Molecularly targeted photothermal ablation improves tumor specificity and immune modulation in a rat model of hepatocellular carcinoma.

Thermal ablation is a standard therapy for patients with hepatocellular carcinoma (HCC). Contemporary ablation devices are imperfect, as they lack tumor specificity. An ideal ablation modality would generate thermal energy only within tumoral tissue.

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

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.

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

"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.