title: Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior.
abstract: Osteosarcoma (OS) is a heterogeneous and rare disease with a disproportionate impact because it mainly affects children and adolescents. Lamentably, more than half of patients with OS succumb to metastatic disease. Clarification of the etiology of the disease, development of better strategies to manage progression, and methods to guide personalized treatments are among the unmet health needs for OS patients. Progress in managing the disease has been hindered by the extreme heterogeneity of OS; thus, better models that accurately recapitulate the natural heterogeneity of the disease are needed. For this study, we used cell lines derived from two spontaneous canine OS tumors with distinctly different biological behavior (OS-1 and OS-2) for heterotypic in vivo modeling that recapitulates the heterogeneous biology and behavior of this disease. Both cell lines demonstrated stability of the transcriptome when grown as orthotopic xenografts in athymic nude mice. Consistent with the behavior of the original tumors, OS-2 xenografts grew more rapidly at the primary site and had greater propensity to disseminate to lung and establish microscopic metastasis. Moreover, OS-2 promoted formation of a different tumor-associated stromal environment than OS-1 xenografts. OS-2-derived tumors comprised a larger percentage of the xenograft tumors than OS-1-derived tumors. In addition, a robust pro-inflammatory population dominated the stromal cell infiltrates in OS-2 xenografts, whereas a mesenchymal population with a gene signature reflecting myogenic signaling dominated those in the OS-1 xenografts. Our studies show that canine OS cell lines maintain intrinsic features of the tumors from which they were derived and recapitulate the heterogeneous biology and behavior of bone cancer in mouse models. This system provides a resource to understand essential interactions between tumor cells and the stromal environment that drive the progression and metastatic propensity of OS.
authors.affiliation: Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Milcah C
authors.identifier: 0000-0003-2151-7335
authors.initials: MC
authors.lastname: Scott
authors.affiliation: Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tomiyasu
authors.affiliation: Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Garbe
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cornax
authors.affiliation: Department of Biomedical Sciences, Center of Emphasis in Cancer Research at the Paul Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Amaya
authors.affiliation: Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Department of Surgery, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Department of Biomedical Sciences, Center of Emphasis in Cancer Research at the Paul Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Brad A
authors.identifier: 0000-0003-1461-9376
authors.initials: BA
authors.lastname: Bryan
authors.affiliation: Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN 55108, USA modiano@umn.edu.|Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN 55108, USA.|Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.|Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.|Center for Immunology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Jaime F
authors.identifier: 0000-0001-6398-7648
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D017154:Stromal Cells / Q000473:pathology; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
keywords: Comparative studies; Heterotypic models; Metastasis; Osteosarcoma; Tumor–stromal interactions; Xenograft