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

转移前生态位进化对循环肿瘤细胞运输的生物物理作用

• 批准号: 10331327
• 负责人: Milos Kojic
• 金额: $ 52.62万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331327
• 关键词: Affect; Aspirin; Biological; Biological Factors; Biophysics; Blood Circulation; Blood Flow Velocity; Blood Platelets; Blood Vessels; Blood capillaries; Blood flow; Cancer Etiology; Cancer Patient; Cell Communication; Cell Line; Cessation of life; Characteristics; Clinic; Computer Models; Data; Deposition; Development; Disease; Distant; Event; Evolution; Future; Image; Immobilization; Immobilized Cells; In Vitro; Label; Liver; Lung; Malignant Neoplasms; Microfluidics; Modeling; Modification; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nonmetastatic; Oncology; Organ; Pathology; Phenotype; Physics; Prevention; Primary Neoplasm; Probability; Process; Reagent; Reporting; Research; Resistance; Risk; Role; Site; System; Testing; Time; Tumor Cell Invasion; base; biophysical properties; cancer cell; imaging study; in silico; in vivo; in vivo imaging; innovation; intravital microscopy; malignant breast neoplasm; metastasis prevention; novel; platelet function; quantitative imaging; recruit; response; tumor; tumor growth

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.

转移性疾病对当前疗法具有抵抗力，并且仍然是与癌症相关死亡的主要原因。 探索促进循环肿瘤细胞（CTC）将来在容器壁上停滞的最早事件 转移地点将暴露于理性预防的新目标。除了生物学因素， CTC的运输和与微环境的相互作用被认为是转移性的关键决定因素 潜在的。最近的研究表明，遥远的微环境已准备就绪并准备捕获CTC，创建 用于启动转移的物转移前利基市场。我们的初步数据显示了时间和器官 肺中肺和肝脏血管的血小板（PLT）积累和激活的增加 乳腺癌，在自发转移到这些器官之前。我们还发现血流速度是 在转移发展之前，肝毛细血管中的异质降低，表明流动的变化 未来转移性部位的血管中的动态可能参与了启动转移的过程。 尽管PLT对癌细胞的直接生物学作用是众所周知的，但PLT在发展中的作用 中转移的利基和这些PLT对CTC生物物理运输机制的影响尚未 报道了。我们的目的是确定通过临时转移的CTC转运的生物物理调制 由PLT使用正交小鼠肿瘤模型，新型微流体和多尺度/多物理学发起的利基市场 计算运输模型。我们的假设是：1）有一个有机和时间依赖的 中转移利基的开发/进化会改变CTC的流体动力学； 2）只 利基市场足够开发以改变这些生物物理参数，促进了CTC在血管上的逮捕 墙； 3）抗PLT试剂对PLT功能的调节会影响PLT在前体内的生物物理作用 CTC运输和转移前景的转移性生态位。多尺度/多物理运输 方法将根据体内和体外的实验结果优化癌症转移的参数化。 为了表征CTC的生物物理转运机制与中转移前的生态位相互作用。 这项研究的意义将建立一个科学框架，以理解中迁移的利基市场的作用 在物理肿瘤学中启动的进化，用于合理预防转移。我们的创新 提案是阐明在CTCS运输中占主导地位的未知生物物理作用并采用 计算肿瘤物理运输模型，结合了多尺度和多物理功能。测试我们的 假设，我们提出以下特定目标（SA）：SA1：了解流动基础 血管与替代前生态位的发展/进化的关系。 SA2：评估生物物理 累积和活化的PLT在替代前生态位中对血管中CTC转运的影响。 SA3：到 确定使用抗PLT试剂对PLT功能的生物物理调节对CTCS转运的影响。