Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior.
Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior.
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DOI：
10.1242/dmm.026849
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发表时间：
2016-12-01
影响因子：
4.3
通讯作者：
Modiano JF
中科院分区：
文献类型：
--
作者：
Scott MC;Tomiyasu H;Garbe JR;Cornax I;Amaya C;O'Sullivan MG;Subramanian S;Bryan BA;Modiano JF
骨肉瘤（OS）是一种异质性和罕见的疾病，其影响不成比例，因为它主要影响儿童和青少年。可悲的是，超过一半的OS患者死于转移性疾病。阐明疾病的病因、制定更好的进展管理策略以及指导个性化治疗的方法是OS患者未满足的健康需求。疾病管理的进展受到OS的极端异质性的阻碍，因此，需要更好的模型，准确地概括疾病的自然异质性。在这项研究中，我们使用来自两种具有明显不同生物学行为的自发性犬OS肿瘤（OS-1和OS-2）的细胞系进行异型体内建模，以重现这种疾病的异质生物学和行为。两种细胞系在无胸腺裸鼠中作为原位异种移植物生长时均表现出转录组的稳定性。与原始肿瘤的行为一致，OS-2异种移植物在原发部位生长得更快，并且更容易扩散到肺部并建立微观转移。此外，OS-2促进了与OS-1异种移植物不同的肿瘤相关基质环境的形成。OS-2衍生的肿瘤比OS-1衍生的肿瘤占异种移植肿瘤的百分比更大。此外，在OS-2异种移植物中，稳健的促炎群体主导基质细胞浸润，而具有反映肌源性信号传导的基因特征的间充质群体主导OS-1异种移植物中的那些。我们的研究表明，犬OS细胞系保持了肿瘤的内在特征，并在小鼠模型中重现了骨癌的异质生物学和行为。该系统提供了一个资源，以了解肿瘤细胞和基质环境之间的基本相互作用，推动OS的进展和转移倾向。编辑的选择：我们开发了一个系统，概括了小鼠模型中骨癌的异质性生物学行为，并描述了研究这些模型中肿瘤-基质相互作用的新方法。
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. Editors' choice: We developed a system that recapitulates the heterogeneous biological behavior of bone cancer in mouse models and describe novel methods to study tumor–stromal interactions in these models.
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影响因子：
12.3
作者：
Creighton C;Kuick R;Misek DE;Rickman DS;Brichory FM;Rouillard JM;Omenn GS;Hanash S
通讯作者：
Hanash S
影响因子：
11.2
作者：
Daniel VC;Marchionni L;Hierman JS;Rhodes JT;Devereux WL;Rudin CM;Yung R;Parmigiani G;Dorsch M;Peacock CD;Watkins DN
通讯作者：
Watkins DN
影响因子：
6
作者：
Delitto, Daniel;Pham, Kien;Trevino, Jose G.
通讯作者：
Trevino, Jose G.
影响因子：
2.7
作者：
Kuijjer ML;Namløs HM;Hauben EI;Machado I;Kresse SH;Serra M;Llombart-Bosch A;Hogendoorn PC;Meza-Zepeda LA;Myklebost O;Cleton-Jansen AM
通讯作者：
Cleton-Jansen AM
影响因子：
48
作者：
Kim D;Langmead B;Salzberg SL
通讯作者：
Salzberg SL