A porcine model of osteosarcoma.

A Saalfrank,U Certa,K-P Janssen,C Brönner,K Flisikowski,A Gnann,T Flisikowska,A Schnieke,I Esposito,A Kind,B Schade,M Ravon,D Saur,B Böhm,E Kappe,É Schulze,P Müller-Fliedner,S Eser,K Steiger

doi:10.1038/oncsis.2016.19

A Saalfrank, U Certa + Show 17 more

Open Access

https://doi.org/10.1038/oncsis.2016.19

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Abstract

We previously produced pigs with a latent oncogenic TP53 mutation. Humans with TP53 germline mutations are predisposed to a wide spectrum of early-onset cancers, predominantly breast, brain, adrenal gland cancer, soft tissue sarcomas and osteosarcomas. Loss of p53 function has been observed in >50% of human cancers. Here we demonstrate that porcine mesenchymal stem cells (MSCs) convert to a transformed phenotype after activation of latent oncogenic TP53R167H and KRASG12D, and overexpression of MYC promotes tumorigenesis. The process mimics key molecular aspects of human sarcomagenesis. Transformed porcine MSCs exhibit genomic instability, with complex karyotypes, and develop into sarcomas on transplantation into immune-deficient mice. In pigs, heterozygous knockout of TP53 was sufficient for spontaneous osteosarcoma development in older animals, whereas homozygous TP53 knockout resulted in multiple large osteosarcomas in 7–8-month-old animals. This is the first report that engineered mutation of an endogenous tumour-suppressor gene leads to invasive cancer in pigs. Unlike in Trp53 mutant mice, osteosarcoma developed in the long bones and skull, closely recapitulating the human disease. These animals thus promise a model for juvenile osteosarcoma, a relatively uncommon but devastating disease.

Highlights

Animal models of human cancers are crucial for the development of urgently needed diagnostic and therapeutic techniques
Work is proceeding towards genetically defined porcine cancer models, such as inactivation of BRCA1 for breast cancer,[6] mutation of TP537 and, as we have reported, knockout and conditional activation of mutant TP53,8 latent oncogenic KRAS mutation[9] and truncating mutations of APC to model colorectal cancer.[10]
We report that targeted mutation of endogenous porcine TP53 and KRAS in primary mesenchymal stem cells (MSCs) results in neoplastic transformation and tumorigenesis

Summary

Introduction

Animal models of human cancers are crucial for the development of urgently needed diagnostic and therapeutic techniques. Modified mice are widely used, but their small size and short lifespan preclude some preclinical studies. It is, for example, difficult to scale down radiological, thermal or surgical treatment of tumours, or perform longitudinal studies of tumour progression and remission, or longer-term response to therapy. Murine cells are more transformed in vitro than human cells,[1] and the set of genetic events required for tumorigenesis is different.[2] Mouse models may not always provide the best representation of human disease. Does replication of single or combined human oncogenic mutation(s) in a pig have an equivalent effect on cell transformation and tumorigenesis?

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