Development of a novel "all-human" animal model to study breast cancer metastasis to bone - comparison of transcriptional signatures from ex vivo cultured primary tumor cells and in vivo metastatic populations.

开发一种新型“全人类”动物模型来研究乳腺癌骨转移 - 比较离体培养的原代肿瘤细胞和体内转移群体的转录特征。

• 批准号: 222945220
• 负责人: Professor Dr. Boris Holzapfel, Ph.D.
• 金额: --
• 依托单位: Klinik und Poliklinik für Orthopädie, Physikalische Medizin und Rehabilitation (Campus Großhadern)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/222945220?language=en
• 关键词: Development; novel; human; animal; model

Currently, treatment options of breast cancer-related metastatic bone disease are usually restricted to palliative therapeutic modalities. Hence, there is a great need to understand the mechanisms of metastatic bone disease at a molecular level. But the currently used in vitro or in vivo models fail to represent the complex composition of the human bone matrix. In order to provide a more appropriate human-specific bone microenvironment, the so-called bone chip model, has been introduced, which relies on the subcutaneous implantation of human bone fragments into severe combined immunodeficient mice. However, this model has major limitations: The bone chip gets poorly vascularized and hence the dead bone does not reflect the real clinical situation. It is very difficult to control size and shape of the bone chip which makes it difficult to establish a reproducible model. The use of tissue engineered constructs could be a highly attractive alternative, since it allows higher reproducibility and control of shape, size and porosity. In the projected study we propose to delineate the comparative transcriptome and methylation profiling of breast cancer cells in models based on 2D & 3D cultures and xenograft tumors in immunocompromised mice. Further, in an in vivo model we propose a novel human tissue engineered bone construct to investigate osteotropism from both sides of the tumor-bone interface in addition to the comparative transcriptome and methylation profiling. This model may recapitulate the metastatic sequence occurring in patients much better than the bone chip model. In addition, we are identifying components within bone stroma essential for metastasis, and osteotropism genes expressed by bone in response to the presence of breast cancer. The proposed research will seek to address important questions in relation to the efficacy of common cancer animal models in the pre-clinical evaluation of human biomarkers and therapeutics.

目前，乳腺癌相关转移性骨疾病的治疗选择通常仅限于姑息治疗方式。因此，在分子水平上了解骨转移性疾病的机制是非常必要的。但目前使用的体外或体内模型不能代表人骨基质的复杂组成。为了提供更合适的人类特异性骨微环境，引入了所谓的骨芯片模型，其依赖于将人骨碎片皮下植入严重联合免疫缺陷小鼠。然而，该模型有很大的局限性：骨片血管化较差，因此死骨不能反映真实的临床情况。骨碎片的大小和形状很难控制，这使得难以建立可重复的模型。组织工程构建体的使用可能是一个非常有吸引力的替代方案，因为它允许更高的再现性和形状，尺寸和孔隙率的控制。 在计划中的研究中，我们建议在基于2D和3D培养物和免疫功能低下小鼠的异种移植肿瘤的模型中描绘乳腺癌细胞的比较转录组和甲基化谱。此外，在体内模型中，我们提出了一种新的人类组织工程化骨构建，除了比较转录组和甲基化谱外，还从肿瘤-骨界面的两侧研究向骨性。该模型可能比骨芯片模型更好地概括患者中发生的转移序列。此外，我们正在鉴定骨基质中对转移至关重要的成分，以及骨对乳腺癌存在的反应中表达的向骨性基因。拟议的研究将寻求解决与常见癌症动物模型在人类生物标志物和治疗方法的临床前评估中的有效性有关的重要问题。