Biophysical roles of pre-metastatic niche evolution on transport of circulating tumor cells

转移性疾病对当前疗法具有耐药性，仍然是癌症相关死亡的主要原因。 探索促进循环肿瘤细胞（CTC）在未来血管壁上停滞的最早事件 转移部位将暴露新的合理预防目标。除了生物因素外， CTC的转运和与微环境的相互作用被认为是转移性肿瘤的关键决定因素。 潜力最近的研究表明，遥远的微环境已经准备好并准备好捕获CTC， 一个转移前的小生境，用于启动转移。我们的初步数据显示 原发性肝癌小鼠肺和肝血管中血小板（PLT）聚集和活化增加 乳腺癌，在自发转移到这些器官之前。我们还发现血流速度 在发生转移之前，肝脏毛细血管不均匀减少，表明血流变化 未来转移部位的血管动力学可能参与启动转移的过程。 尽管PLT对癌细胞的直接生物学效应是众所周知的，但PLT在肿瘤发生发展中的作用仍有待进一步研究。 转移前的小生境和这些PLT对CTC的生物物理转运机制的影响还没有 被举报。我们的目的是确定转移前肿瘤细胞对CTC转运的生物物理调节。 使用正交各向异性小鼠肿瘤模型、新型微流体和多尺度/多物理学由PLT启动的生态位 计算运输模型。我们的假设是：1）存在器官和时间依赖性 转移前小生境的发展/演变改变了CTC的流体动力学; 2）仅转移前小生境的发展/演变改变了CTC的流体动力学。 充分发展以改变这些生物物理参数的生态位促进血管上CTC的阻滞 3）抗PLT试剂对PLT功能的调节影响了PLT在预处理中的生物物理作用。 转移小生境对CTC转运的影响及转移的前景。多尺度/多物理场输运 该方法将基于体内和体外实验结果优化癌症转移的参数化， 以表征CTC与转移前小生境相互作用的生物物理转运机制。 本研究的意义将建立一个科学的框架，了解转移前的小生境的作用 在物理肿瘤学中以PLT开始的进化，用于合理预防转移。我们的创新 一项建议是阐明转移前小生境对CTC转运的未知生物物理作用，并采用 结合多尺度和多物理能力的计算物理传输模型。来测试我们 假设，我们提出了以下具体目标（SA）：SA 1：了解流动的基本原理， 血管作为转移前小生境的发展/演变的函数。SA 2：评价生物物理学 转移前小生境中积聚和活化的PLT对血管中CTC转运的影响。SA 3：至 使用抗PLT试剂确定PLT功能的生物物理调节对CTC转运的影响。

Metastatic disease is resistant to current therapies and remains the primary cause of cancer-related death. Exploring the earliest events that promote circulating tumor cells (CTCs) to arrest on vessel wall at future metastatic sites will expose new targets for rational prevention. In addition to biological factors, the physical transport of CTCs and interactions with the microenvironment are regarded as key determinants of the metastatic potential. Recent studies suggest that distant microenvironments are primed and ready to entrap CTCs, creating a pre-metastatic niche for initiating metastasis. Our preliminary data shows a time- and organ-dependent increase in platelet (PLT) accumulation and activation in vessels of both lung and liver in mice bearing primary breast cancer, prior to spontaneous metastasis to these organs. We also found blood flow velocity was heterogeneously reduced in capillaries of the liver before development of metastasis, indicating changes in flow dynamics in vessels of the future metastatic sites may be involved in the process of initiating metastasis. Whereas direct biological effects of PLT on cancer cells are well known, the roles of PLT in the development of the pre-metastatic niche and the effects of these PLTs on biophysical transport mechanisms of CTCs have not been reported. Our objective is to determine biophysical modulation of CTC transport by the pre-metastatic niche initiated by PLTs using orthotropic mouse tumor models, novel microfluidics, and multiscale/multi-physics computational transport models. Our hypotheses are: 1) there is an organ- and time-dependent development/evolution of the pre-metastatic niche alters hydrodynamics for CTCs; 2) only the pre-metastatic niche, which is sufficiently developed to alter these biophysical parameters, promotes arrest of CTCs on vessel walls; and 3) modulation of PLT functionality by anti-PLT reagents affects biophysical roles of PLTs in the pre- metastatic niche on CTC transport and the prospect of metastasis. The multiscale/multi-physics transport approach will optimize parameterization of cancer metastasis based on experimental results in vivo and in vitro, in order to characterize biophysical transport mechanisms of CTCs interacting with pre-metastatic niche. Significance of this study will establish a scientific framework for understanding roles of the pre-metastatic niche evolution initiated with PLTs in physical oncology for rational prevention of metastasis. Innovation of our proposal is to elucidate unknown biophysical roles of the pre-metastatic niche on CTCs transport and to employ computational oncophysical transport model incorporating multi-scale and multi-physics capabilities. To test our hypothesis, we propose the following Specific Aims (SA): SA1: To understand the flow fundamentals in vessels as a function of development/evolution of the pre-metastatic niche. SA2: To evaluate the biophysical effect of accumulated and activated PLTs in the pre-metastatic niche on CTC transport in vessels. SA3: To determine the effect of biophysical modulation of PLT functions on CTCs transport using anti-PLT reagents.