Center for Modeling Tumor Cell Migration Mechanics

肿瘤细胞迁移机制建模中心

基本信息

批准号：
9187771
负责人：
DAVID ANDREW LARGAESPADA
金额：
$ 166.7万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-17 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187771
关键词：
Affect Animal Model Animals Attention Automobile Driving Beryllium Biomechanics Biomedical Engineering Biomedical Technology Cancer Center Cancer Etiology Cancer Immunology Science Cancer Patient Carcinoma Cell Proliferation Cell division Cell model Cells Cessation of life Characteristics Chemistry Cities Clinic Clinical Clinical Trials Complex Computer Simulation Disease Disease Progression Drug resistance Education and Outreach Elements Engineering Environment Funding Future Genetic Genetic Screening Genome engineering Geographic Locations Goals Human Immune Immune response In Vitro Inflammation Institutes Investments Lead Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of pancreas Mathematics Mayo Clinic Cancer Center Mechanics Microfluidics Modeling Molecular Molecular Genetics Molecular Motors Motor Mus Mutate Mutation Neoplasm Metastasis Oncogenes Oncologist Pathway interactions Phenotype Physics Premalignant Process Proteins Publishing Science Side Signal Pathway Staging Suppressor-Effector T-Lymphocytes System T-Lymphocyte Testing The Cancer Genome Atlas Therapeutic Time Tissue Engineering Traction Tumor Biology Tumor Cell Migration Tumor Subtype Tumor-Derived Twin Multiple Birth Wood material Work abstracting actionable mutation base biomathematics cancer cell cancer genetics cancer genome cancer type cell behavior cell motility clinically relevant design extracellular gene discovery gene therapy genetic approach genome sequencing human disease in vivo macrophage microsystems migration molecular mechanics multidisciplinary neoplastic cell new therapeutic target novel therapeutic intervention oncology patient stratification research study reverse genetics success treatment strategy tumor tumor microenvironment tumor progression unpublished works

项目摘要

Abstract At their most fundamental level, cancers are initiated by genetic alterations that drive hyperactive cell division and cell migration. A common therapeutic strategy has been to target the proteins in the often-mutated signaling pathways that regulate cell proliferation. However, so far this strategy has achieved only limited success despite large public and private investment, which is likely due to functional redundancies in signaling pathways that give multiple avenues for the emergence of drug-resistance. An alternative strategy, which defines the organizing framework of our Center, is to directly target the internal or external mechanical machinery or structural elements that drive cell migration. As it is these elements that serve as the most downstream convergence point of the upstream genetic alterations, disruption of these critical elements provides viable, clinically-relevant targets. Since cell migration is a common feature of high-grade cancer, and invasion and metastasis are the primary cause of cancer related death, our Center will focus on understanding the fundamental mechanics and chemistry of how cells generate forces to move through complex and mechanically challenging tumor microenvironments. By focusing directly on the “nuts and bolts” of cell migration, we will be targeting the most vital and non-redundant part of the system. Specifically, we propose integrated modeling and experiments to investigate the molecular mechanics of cell migration and how the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. We will experimentally test our computational cell migration simulator, v1.0 (CMS1.0) for the mechanical dynamics of cell migration that will ultimately be used to: 1) identify novel drug targets/target combinations in silico, 2) define molecular mechanical subtypes of tumors for patient stratification, 3) guide the engineering of in vitro microsystems and in vivo animal models to better mimic the human disease, and 4) simulate tumor progression under different potential treatment strategies. Finally, we will develop a simulator-driven reverse genetics approach to elucidate the functional mechanical consequences of driver mutations and seek to manipulate the physical characteristics of a tumor to simultaneously bias against immune suppressor cells and promote the antitumor immune response.

抽象的在最基本的水平上，癌症是通过驱动多动细胞分裂的遗传改变引发的和细胞迁移。一种共同的理论策略是针对经常突破的蛋白质调节细胞增殖的信号通路。但是，到目前为止，该策略仅达到有限成功目的地大型公共和私人投资，这可能是由于信号的功能冗余而引起的为抗药性出现提供了多种途径的途径。另一种策略，该策略定义我们中心的组织框架是直接针对内部或外部机械的驱动细胞迁移的机械或结构元素。因为这些元素是最大的上游遗传改变的下游收敛点，这些关键元素的破坏提供可行的，临床上与临床相关的目标。由于细胞迁移是高级癌症的常见特征，并且入侵和转移是癌症相关死亡的主要原因，我们的中心将专注于理解细胞如何产生力量通过复合物和化学的基本力学和化学机械挑战肿瘤微环境。通过直接关注细胞的“坚果和螺栓” 迁移，我们将针对系统中最重要和最冗余的部分。具体来说，我们建议集成建模和实验，以研究细胞迁移的分子机制以及如何肿瘤微环境调节疾病的进展是潜在的癌遗传学的函数。我们将通过实验测试我们的计算细胞迁移模拟器V1.0（CMS1.0）的机械动力学最终将用于以下方式的细胞迁移：1）识别硅中的新型药物靶/靶标组合，2）定义用于患者分层的肿瘤的分子机械亚型，3）指导体外工程微生系统和体内动物模型以更好地模仿人类疾病，4）模拟肿瘤在不同的潜在治疗策略下进展。最后，我们将开发一个模拟器驱动的反向阐明驱动器突变的功能机械后果的遗传学方法并寻求操纵肿瘤的身体特征，以同时偏向免疫抑制剂细胞和促进抗卧底免疫反应。