Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior

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 man...

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Main Authors:	Scott, Milcah C., Tomiyasu, Hirotaka, Garbe, John R., Cornax, Ingrid, Amaya, Clarissa, O'Sullivan, M. Gerard, Subramanian, Subbaya, Bryan, Brad A., Modiano, Jaime F.
Format:	Online
Language:	English
Published:	The Company of Biologists Ltd 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200896/

id	pubmed-5200896
recordtype	oai_dc
spelling	pubmed-52008962017-01-13 Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior Scott, Milcah C. Tomiyasu, Hirotaka Garbe, John R. Cornax, Ingrid Amaya, Clarissa O'Sullivan, M. Gerard Subramanian, Subbaya Bryan, Brad A. Modiano, Jaime F. Research Article 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. The Company of Biologists Ltd 2016-12-01 /pmc/articles/PMC5200896/ /pubmed/27874835 http://dx.doi.org/10.1242/dmm.026849 Text en © 2016. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Scott, Milcah C. Tomiyasu, Hirotaka Garbe, John R. Cornax, Ingrid Amaya, Clarissa O'Sullivan, M. Gerard Subramanian, Subbaya Bryan, Brad A. Modiano, Jaime F.
spellingShingle	Scott, Milcah C. Tomiyasu, Hirotaka Garbe, John R. Cornax, Ingrid Amaya, Clarissa O'Sullivan, M. Gerard Subramanian, Subbaya Bryan, Brad A. Modiano, Jaime F. Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
author_facet	Scott, Milcah C. Tomiyasu, Hirotaka Garbe, John R. Cornax, Ingrid Amaya, Clarissa O'Sullivan, M. Gerard Subramanian, Subbaya Bryan, Brad A. Modiano, Jaime F.
author_sort	Scott, Milcah C.
title	Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
title_short	Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
title_full	Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
title_fullStr	Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
title_full_unstemmed	Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
title_sort	heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior
description	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.
publisher	The Company of Biologists Ltd
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200896/
_version_	1613847303229014016

Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior

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