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Exploring the effects of extracellular fluid viscosity on cell migration and cancer metastasis

探索细胞外液粘度对细胞迁移和癌症转移的影响

基本信息

批准号：
10338078
负责人：
Matthew Pittman
金额：
$ 4.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338078
关键词：
3-Dimensional Actins Actomyosin Affect Aging Albumins Area Biological Blood Circulation Body Fluids Cancer Patient Cancerous Cell Line Cell physiology Cells Chronic lung disease Coculture Techniques Collagen Complex Cues Cystic Fibrosis Cytoskeleton Development Disease Disease Progression Elderly Environment Epithelial Epithelial Cells Event Extracellular Fluid Extracellular Matrix Extracellular Protein Fibrinogen Fibroblasts Fibrosis Fluorescence Focal Adhesions Hydrostatic Pressure Infiltration Inflammation Integrins Intercellular Fluid Intervention Lead Life Liquid substance Lymph Malignant Neoplasms Malignant neoplasm of lung Measurement Measures Mechanics Mediating Membrane Mesenchymal Methylcellulose Microscopy Modeling Molecular Mucins Mucous body substance Neoplasm Metastasis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Physical environment Physiological Plasma Plasma Proteins Play Process Protein Secretion Resistance Role Saliva Sampling Signal Transduction Speed Structure of parenchyma of lung Surface Surveys System Testing Time Tissues Traction Variant Viscosity Water base cancer cell cell motility cell type dosage extracellular genetic manipulation idiopathic pulmonary fibrosis improved interstitial macrophage migration mimicry neutrophil novel therapeutics overexpression pathogen polymerization response stem cell differentiation tumor microenvironment wound wound healing

项目摘要

PROJECT SUMMARY Mechanical cues and the local physical environment play fundamental roles in a host of cellular processes, ranging from stem cell differentiation to cell motility. While the significance of the stiffness of the extracellular microenvironment has been well-studied, the role of others physical factors, such as fluid viscosity and hydrostatic pressure, are less understood. The viscosities of biological fluids span orders of magnitude, and due to lymph circulation, disease development, and fluctuations in protein secretion, cells directly in contact with mucus, extracellular fluid (ECF), and saliva are often subjected to variations in viscosity. Additionally, abnormal ECF viscosity is associated with diseases such as cystic fibrosis, idiopathic pulmonary fibrosis, and cancer. In the context of cancer, leaky vasculature and matrix degradation within the tumor microenvironment lead to high local concentrations of plasma proteins and soluble collagen that could increase ECF viscosity. Moreover, mucins, the large, heavily-glycosylated extracellular proteins responsible for the high viscosity of mucus and saliva, are overexpressed in many malignancies. Despite that higher mucus/ECF viscosity is observed in chronic lung disease and cancer patients, it is not well studied, that how cells are further affected by the altered viscosity, as well as how altered viscosity can additionally promote the disease progression. A recent study revealed that counterintuitively cell migration speed increases in mesenchymal-like cell lines, as the cells navigate the aquatic environment of higher viscosity. I plan to characterize the effects of high viscosity in multiple cell types and cocultures that are physiologically relevant, to identify the mechanisms behind the changes in cell motility and cytoskeleton dynamics to elevated viscosity, and to build a quantitative model to predict the effect of viscosity in cell migration, and to predict the effect of potential pharmaceutical perturbations.

项目总结机械提示和当地物理环境在许多细胞过程，从干细胞分化到细胞运动。虽然它的意义在于细胞外微环境的刚性已经得到了很好的研究，其他因素的作用也是如此物理因素，如流体粘度和流体静压，则知之甚少。这个生物体液的粘度跨越数量级，由于淋巴循环，疾病发育和蛋白质分泌的波动，细胞直接与粘液接触，细胞外液(ECF)和唾液经常受到粘度变化的影响。另外， ECF粘度异常与囊性纤维化、特发性肺纤维化等疾病有关纤维化症和癌症。在癌症的背景下，血管渗漏和基质降解肿瘤微环境导致局部血浆蛋白和可溶性蛋白浓度较高能增加ECF粘度的胶原蛋白。此外，粘蛋白是一种大的、高度糖基化的导致粘液和唾液高粘度的胞外蛋白过度表达在许多恶性肿瘤中。尽管如此，在慢性肺中观察到较高的粘液/ECF粘度对于疾病和癌症患者，细胞如何进一步受到粘度变化，以及粘度变化如何进一步促进疾病进步。最近的一项研究显示，与直觉相反，细胞迁移速度在间充质样细胞系，随着细胞在较高粘度的水环境中航行。我计划在多种细胞类型和共培养中表征高粘度的影响与生理相关，以确定细胞运动性变化背后的机制和细胞骨架动力学，以提高粘度，并建立一个定量模型来预测黏度对细胞迁移的影响，并预测潜在药物的影响微扰。