Abstract
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 KRASG12D and TP53R167H 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.
Highlights
Human tumor-derived cell lines play an important role in the discovery and development of new cancer therapies[5]
KRAS is rarely mutated in human STS3, TP53 is among the most frequently mutated genes identified[13, 14], and deregulation of both TP53 and KRAS signaling pathways is commonly utilized to produce sarcoma animal models[8, 14]
Primary fibroblast cell lines were treated with adenoviral particle vectors encoding Cre recombinase (AdCre), resulting in the transformation of cells in culture[12]
Summary
Human tumor-derived cell lines play an important role in the discovery and development of new cancer therapies[5]. The Oncopig model encodes Cre recombinase inducible porcine transgenes encoding KRASG12D and TP53R167H, which represent a commonly mutated oncogene and tumor suppressor in human cancers, respectively[12] This allows the Oncopig to model a wide variety of human sarcomas in an inducible, temporal manner. KRAS is rarely mutated in human STS3, TP53 is among the most frequently mutated genes identified[13, 14], and deregulation of both TP53 and KRAS signaling pathways is commonly utilized to produce sarcoma animal models[8, 14] This strategy has been used to develop a porcine model that produces spontaneous osteosarcomas due to constitutive TP53R167H expression[15]. The results presented here demonstrate the validity of the Oncopig model to mimic human STS on the transcriptomic level, providing further validation for the use of the Oncopig in sarcoma research
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