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research study reverse genetics success treatment strategy tumor tumor microenvironment tumor progression unpublished works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.

抽象的在最基本的层面上，癌症是由驱动细胞分裂过度的基因改变引发的常见的治疗策略是针对经常突变的蛋白质。然而，到目前为止，这种策略仅取得了有限的成果。尽管有大量公共和私人投资，但仍取得了成功，这可能是由于信号方面的功能冗余为耐药性的出现提供多种途径的另一种策略。定义了我们中心的组织框架，是直接针对内部或外部的机械驱动细胞迁移的机械或结构元件，因为这些元件是最重要的。上游遗传改变的下游汇聚点，这些关键元素的破坏提供可行的、临床相关的目标，因为细胞迁移是高级癌症的共同特征，并且侵袭和转移是癌症相关死亡的主要原因，我们中心将重点了解细胞如何产生力以穿过复杂的环境的基本力学和化学通过直接关注细胞的“具体细节”，对肿瘤微环境提出机械挑战。迁移时，我们将针对系统中最重要且非冗余的部分。具体来说，我们建议。集成建模和实验来研究细胞迁移的分子力学以及如何肿瘤微环境作为潜在癌症遗传学的功能调节疾病进展。将通过实验测试我们的计算细胞迁移模拟器 v1.0 (CMS1.0) 的机械动力学细胞迁移最终将用于：1）在计算机中识别新的药物靶点/靶点组合，2）定义肿瘤的分子力学亚型以进行患者分层，3）指导体外工程微系统和体内动物模型，以更好地模拟人类疾病，以及4）模拟肿瘤最后，我们将开发模拟器驱动的逆转。遗传学方法阐明驱动突变的功能机械后果并寻求操纵肿瘤的物理特性，同时偏向免疫抑制细胞和促进抗肿瘤免疫反应。