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

Schachtschneider, Kyle M.; Liu, Yingkai; Mäkeläinen, Suvi; Madsen, Ole; Rund, Laurie A.; Groenen, Martien A. M.; Schook, Lawrence B.

doi:10.1038/s41598-017-02912-9

Cited by 22 publications

(22 citation statements)

References 63 publications

(88 reference statements)

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“…In addition, FOSL1 , a key transcriptional regulator of human STS, was identified as a master regulator in the Oncopig STS cell lines ( 76 ), further demonstrating the similarities between Oncopig and human STS at the molecular level. These in vitro phenotypes and transcriptional profiles are consistent across replicates and in lines cultured for extended periods of time ( 76 ), highlighting the stability of Oncopig cell lines. As the OCM supports the transformation of any cell type, it provides a platform for the production of stable STS cell lines originating from a wide variety of mesenchymal cell types for in vitro STS research.…”

Section: The Ocmmentioning

confidence: 89%

“…As TP53 represents one of the most frequently mutated genes in human STS ( 92 , 93 ), the OCM represents an ideal model to develop STS cell lines and in vivo models critical for improving survival rates for patients with STS. To date, both STS cell lines and in vivo STS tumors have been developed and characterized in the OCM ( 76 , 87 ).…”

Section: The Ocmmentioning

confidence: 99%

“…The resulting STS cell lines expressed both KRAS G12D and TP53 R167H transgenes and displayed tumorigenic phenotypes, including altered morphology, reduced cell cycle length, increased cell migration, and soft agar colony formation ( 87 ). Injection of the STS cell lines in SCID mice resulted in tumor formation ( 87 ), and transcriptional profiling of Oncopig STS cell lines via RNA-seq identified transcriptional hallmarks of human STS, including altered TP53 signaling, Wnt signaling activation, and evidence of epigenetic reprogramming, including altered expression of DNA and histone methyltransferases ( 76 ). In addition, FOSL1 , a key transcriptional regulator of human STS, was identified as a master regulator in the Oncopig STS cell lines ( 76 ), further demonstrating the similarities between Oncopig and human STS at the molecular level.…”

Section: The Ocmmentioning

confidence: 99%

“…Injection of the STS cell lines in SCID mice resulted in tumor formation ( 87 ), and transcriptional profiling of Oncopig STS cell lines via RNA-seq identified transcriptional hallmarks of human STS, including altered TP53 signaling, Wnt signaling activation, and evidence of epigenetic reprogramming, including altered expression of DNA and histone methyltransferases ( 76 ). In addition, FOSL1 , a key transcriptional regulator of human STS, was identified as a master regulator in the Oncopig STS cell lines ( 76 ), further demonstrating the similarities between Oncopig and human STS at the molecular level. These in vitro phenotypes and transcriptional profiles are consistent across replicates and in lines cultured for extended periods of time ( 76 ), highlighting the stability of Oncopig cell lines.…”

Section: The Ocmmentioning

confidence: 99%

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

et al. 2017

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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, TP53R167H and KRASG12D, 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.

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Section: The Ocmmentioning

confidence: 89%

Section: The Ocmmentioning

confidence: 99%

Section: The Ocmmentioning

confidence: 99%

Section: The Ocmmentioning

confidence: 99%

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

et al. 2017

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“…Complementing spontaneous tumor models in pet dogs, the development of genetically modified pigs has allowed for several tumor types to be studied in these large experimental animal models. In particular, basal cell carcinoma, 186 colorectal cancer, 187 breast cancer, 189,190 soft-tissue sarcoma, 191,223 hepatocellular carcinoma, 198 pancreatic ductal adenocarcinoma (Principt et al, 2018, submitted), lymphoma, 193 and osteosarcoma 193,197 (Table 3) are among the tumor types that are currently in focus. However and as previously mentioned, both the colorectal cancer 187,188 and breast cancer 189,190 models currently either lack in vivo tumor development or display issues with lethality.…”

Section: Ongoing and Future Translational Opportunitiesmentioning

confidence: 99%

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

et al. 2018

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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.

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

et al. 2021

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

Cited by 22 publications

References 63 publications

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

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

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

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

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