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

Gaba, Ron C.; Elkhadragy, Lobna; Boas, F.; Chaki, Sulalita; Chen, Hanna H.; El-Kebir, Mohammed; García, Kelly; Giurini, Eileena F.; Guzman, Grace; LoBianco, Francesca V.; Neto, Mário F.; Newson, Jordan; Qazi, Aisha; Regan, Meredith M.; Rund, Lauretta A.; Schwind, Regina M.; Stewart, Margaret M.; Thomas, Faith M.; Whiteley, Herbert E.; Wu, Jiaqi; Schook, Lawrence B.; Schachtschneider, Kyle M.

doi:10.18632/oncotarget.27647

Cited by 21 publications

(21 citation statements)

References 42 publications

(22 reference statements)

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“…Recently published data has also shown the oncopig tumor holds a heterogeneous population of tumor hepatocellular carcinoma cells. The results indicate the presence of intratumor heterogeneity resulted from the accumulation of somatic mutations in distinct tumor cells as commonly observed in human HCC (Gaba et al, 2020). Finally, the OCM showed that expression of TP53 R167H and KRAS G12D generated tumors that recapitulated transcriptional characteristics found in human soft tissue sarcomas (Schachtschneider et al, 2017a).…”

Section: Perspective: Humanized Swine Models Of Bcmentioning

confidence: 62%

Perspective: Humanized Pig Models of Bladder Cancer

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et al. 2021

Front. Mol. Biosci.

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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.

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Section: Perspective: Humanized Swine Models Of Bcmentioning

confidence: 62%

Perspective: Humanized Pig Models of Bladder Cancer

Segatto

Bender

Seixas

et al. 2021

Front. Mol. Biosci.

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“…Second, although TP53 driver mutations are commonly observed in clinical HCC, the KRAS driver mutation is rarely observed in HCC ( Hussain et al, 2007 ; Turhal et al, 2015 ). However, previous publications have demonstrated that Oncopig HCC recapitulates human HCC in terms of transcriptional profiles, histological phenotypes, AFP expression, proliferation rates, migration rates, and chemotherapeutic susceptibilities ( Schachtschneider et al, 2017a ; Gaba et al, 2020 ). Therefore, despite the presence of a KRAS driver mutation, the Oncopig HCC model represents a clinically relevant large animal HCC model.…”

Section: Discussionmentioning

confidence: 99%

“…Primary hepatocytes were isolated and transformed into HCC cells from Oncopig liver tissues ( n = 2 female, n = 1 male) as previously described ( Schachtschneider et al, 2017a ; Gaba et al, 2020 ). Briefly, primary hepatocytes were isolated from resected Oncopig liver tissues.…”

Section: Methodsmentioning

confidence: 99%

“…Advances in cancer research are reliant on the use of novel, clinically relevant preclinical cancer models. Recently the Oncopig Cancer Model—a novel transgenic swine model that recapitulates human cancer through Cre recombinase induced expression of KRAS G 12 D and TP53 R 167 H driver mutations ( Schook et al, 2015 )—has been validated as a large animal translational model for human HCC ( Schachtschneider et al, 2017a ; Gaba et al, 2020 ). The similar size, anatomy, physiology, immunology, metabolism, genetics, and epigenetics between pigs and humans allows for translation of results to clinical practice to improve diagnostics and therapeutic applications ( Schachtschneider et al, 2017b ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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 KRASG12D and TP53R167H 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 (n = 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 in vivo, improving our understanding of the interplay between HCC tumor cells, the surrounding tumor microenvironment, and the impact on HCC development and progression.

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“…The medium was changed to DMEM containing 10% FBS at 4 h post-transduction. Expression of the transgene and hepatocellular origin of the cells were confirmed by RT-PCR and arginase-1 staining, respectively, as previously described [4,5].…”

Section: Generation Of Porcine Hcc Cellsmentioning

confidence: 99%

Generation of Genetically Tailored Porcine Liver Cancer Cells by CRISPR/Cas9 Editing

et al. 2020

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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 TP53R167H and KRASG12D 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 in vivo testing of novel targeted therapeutic approaches in a clinically relevant large animal model.

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

Cited by 21 publications

References 42 publications

Perspective: Humanized Pig Models of Bladder Cancer

Perspective: Humanized Pig Models of Bladder Cancer

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

Generation of Genetically Tailored Porcine Liver Cancer Cells by CRISPR/Cas9 Editing

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