title: A porcine model of osteosarcoma.
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 TP53(R167H) and KRAS(G12D), 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.
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Saalfrank
authors.affiliation: Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: K-P
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Ravon
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Flisikowski
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Eser
authors.affiliation: Department of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Flisikowska
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Müller-Fliedner
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: É
authors.initials: É
authors.lastname: Schulze
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Brönner
authors.affiliation: Department of Surgery, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gnann
authors.affiliation: Department of Pathology, Bavarian Animal Health Service, Poing, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Kappe
authors.affiliation: Department of Pathology, Bavarian Animal Health Service, Poing, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Böhm
authors.affiliation: Department of Pathology, Bavarian Animal Health Service, Poing, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Schade
authors.affiliation: Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: U
authors.initials: U
authors.lastname: Certa
authors.affiliation: Department of Medicine II, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Saur
authors.affiliation: Institute of Pathology, Heinrich-Heine-University of Düsseldorf, Düsseldorf, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kind
authors.affiliation: Chair of Livestock Biotechnology, Technische Universität München, Freising, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schnieke