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Systems Bioengineering of Cancer Cell Migration

癌细胞迁移的系统生物工程

基本信息

批准号：
9068869
负责人：
JENNIFER Jean LINDERMAN
金额：
$ 43.44万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9068869
关键词：
Advanced Malignant Neoplasm Animal Model Architecture Binding Biology Biomedical Engineering Blood Vessels Breast Breast Cancer Cell CXCL12 gene CXCR4 gene Cancer Biology Carcinoma Cells Cessation of life Complex Computer Simulation Cytoskeleton Data Deformity Development Device Designs Devices Disease Disease Progression Disseminated Malignant Neoplasm Distant Metastasis Duct (organ) structure Engineering Environment Excision Extracellular Matrix Extravasation Fibroblasts Forms Controls Future Geometry Health Histology Human Image Immigration In Situ In Vitro Intervention Invaded Knowledge Lead Lymphatic Malignant Neoplasms Mammary Gland Parenchyma Mediating Methods Microfluidic Microchips Microinvasive Modeling Neoplasm Metastasis Normal tissue morphology Operative Surgical Procedures Outcome Pathway interactions Patients Physiology Positioning Attribute Postoperative Period Printing Process Protein Isoforms RNA Splicing Recurrence Research Residual Tumors Resistance Risk Route Shapes Signal Transduction Signaling Molecule Site Stromal Cells Structure Surface System Technology Testing Tissues Xenograft procedure base cancer cell cell motility cell type chemokine directional cell extracellular high risk in vitro Model in vivo inhibitor/antagonist innovation intravital microscopy lymph nodes malignant breast neoplasm meetings migration molecular/cellular imaging prevent response treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Directional migration of malignant cells toward a gradient of one or more signaling molecules underlies fundamental steps in metastasis, including local invasion of cancer cells, vascular intravasation, and extravasation of cancer cells at secondary sites. Understanding formation of gradients in complex environments with multiple cells and extracellular matrix molecules remains a central challenge in cell migration not only in cancer but also in normal physiology and other diseases. The challenge of understanding gradient formation and cell migration becomes even more difficult in the disordered cellular and extracellular matrix architecture of a tumor. We will meet this challenge through an integrated systems bioengineering approach combining microscale technologies for cell migration, in vitro and in vivo cellular and molecular imaging, and sophisticated multi-scale computational models. This approach will enable us to investigate gradient formation and cell migration in increasingly complex environments, ranging from a 2D system with defined positions of three different cell types to the disorganized structure of a tumor. Using computational modeling to identify key parameters controlling gradient formation and cell migration, we also will experimentally test and validate interventions to block cell migration, which will provide new targets for anti-metastatic therapies. Our research will focus on gradient formation and cell migration controlled by chemokine CXCL12, a signaling molecule that drives metastasis in more than 20 human cancers. CXCL12 exists as six alternatively-spliced isoforms, four of which are expressed in human breast cancers. We recently have shown CXCL12-isoform specific differences in cell migration, resistance to targeted inhibitors, and correlations with disease recurrence and survival in breast cancer. We propose that CXCL12 molecules bound to the extracellular environment drive cell migration, a process referred to as haptotaxis, and differences in binding to the extracellular matrix underlie isoform-specific differences in gradient formation and cell migration. To investigate CXCL12 isoforms in cell migration, we will complete the following specific aims: 1) derive basic cell migration response parameters under simple, defined gradients; 2) using tissue-like geometries, test effects of extracellular matrix composition on migration potency of CXCL12 isoforms; and 3) Quantify in vivo migration in tumor environments with different CXCL12 isoforms. Collectively, this research will advance knowledge of gradient formation in cell migration and point to new treatment strategies for targeting CXCL12 in cancer.