Probing Contact Guidance on Exquisitely Tunable ECM Surfaces

精确可调 ECM 表面上的探测接触指南

• 批准号: 8684564
• 负责人: Ian Christopher Schneider
• 金额: $ 6.91万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8684564
• 关键词: Address; Adhesions; Axilla; Behavior; Binding; Binding Proteins; Biopsy; Breast Carcinoma; Cell Adhesion; Cells; Characteristics; Collagen; Collagen Fiber; Collagen Type IV; Cues; Deposition; Diagnosis; Diagnostic; Engineering; Environment; Exhibits; Extracellular Matrix; Fiber; Fibronectins; Film; Future; Gel; Goals; Growth; Heparin; Hybrids; Image; Imaging Techniques; Immigration; Immune; Individual; Laminin; Lead; Life; Link; Magnetism; Malignant Epithelial Cell; Malignant Neoplasms; Measurement; Measures; Mechanics; Mica; Microscopy; Modeling; Mus; Positioning Attribute; Probability; Property; Proteins; Proxy; Relative (related person); Research; Research Personnel; Role; Specific qualifier value; Speed; Staining method; Stains; Stromal Neoplasm; Structure; Surface; System; Testing; Variant; Work; biophysical properties; cancer cell; cell motility; crosslink; density; in vivo; insight; migration; outcome forecast; prognostic; public health relevance; tumor; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): It has been long appreciated that changes in the extracellular matrix (ECM) in the tumor microenvironment can drive tumor progression. With the recent advance in imaging techniques changes in the organization of ECM components like collagen have been described. Circumferentially organized collagen fibers are reorganized into radially aligned fibers, leading to directed migration or contact guidance away from the tumor. This collagen organizational signature has been proposed as a diagnostic indicator of potential invasion, linking contact guidance to invasion. Unfortunately, while there is an abundance of information on contact guidance in 2D environments, much less is known about contact guidance in 3D environments. In addition, collagen fiber networks can exhibit a large variation in properties separate from alignment that regulate the ability of cells to sense and respond to contact guidance cues, effectively altering the relationship between collagen organization and invasion. My long-term goal is to understand how tumor, stromal and immune cells integrate multiple cues for directional migration in the tumor microenvironment by using various engineering approaches. The objective of this research is to understand the role of the organization and composition of collagen I matrix in directing contact guidance. The specific aims of this proposal include: (1) Assess the relative contributions of topology and confinement in explaining the differences between contact guidance in 2D and 3D environments, (2) Test the hypothesis that changes in fiber structure such as fiber and crosslinking density as well as degree of alignment regulate the contact guidance of cancer cells and (3) Test the hypothesis that collagen I binding proteins that promote adhesion or de-adhesion regulate the contact guidance of cancer cells. Epitaxial growth of collagen fibers on mica as well as magnetic alignment of collagen fibers in gels will be used to engineer environments with specify contact guidance characteristics. Cell migration will be assessed using live cell microscopy in 2D, 3D and hybrid environments. Understanding how different properties of collagen fiber networks regulate contact guidance will further refine the prognostic ability of diagnostic biopsy images. Quantification of collagen fiber density, measurement of mechanical properties of the biopsy, a proxy for crosslinking density, and staining of additional collagen binding partners will give insight into the efficiency of contact guidance away from an individual tumor. Future work will be geared towards making these measurements in vivo and in biopsies from mouse tumor models and correlating these biophysical and compositional properties to tumor progression or prognosis.

描述（由申请人提供）：长期以来，人们已经认识到肿瘤微环境中细胞外基质（ECM）的变化可以驱动肿瘤进展。随着成像技术的最新进展，已经描述了ECM组分如胶原蛋白的组织变化。环周组织的胶原纤维重组成径向排列的纤维，导致定向迁移或接触引导远离肿瘤。这种胶原组织特征已被提出作为潜在入侵的诊断指标，将接触指导与入侵联系起来。不幸的是，虽然在2D环境中有大量关于接触引导的信息，但关于3D环境中的接触引导知之甚少。此外，胶原纤维网络可以表现出与对齐分开的性质的大的变化，其调节细胞感知和响应接触引导线索的能力，有效地改变胶原组织和侵入之间的关系。我的长期目标是了解肿瘤，基质和免疫细胞如何通过使用各种工程方法整合肿瘤微环境中定向迁移的多种线索。本研究的目的是了解I型胶原基质的组织和组成在直接接触引导中的作用。这项建议的具体目标包括：（1）评估拓扑和限制在解释2D和3D环境中的接触引导之间的差异方面的相对贡献，（2）检验纤维结构如纤维和交联密度以及排列程度的变化调节癌细胞的接触引导的假设，以及（3）检验促进粘附或去粘附的I型胶原结合蛋白调节癌细胞的接触引导的假设。胶原纤维在云母上的外延生长以及胶原纤维在凝胶中的磁性排列将用于设计具有特定接触引导特性的环境。将在2D、3D和混合环境中使用活细胞显微镜评估细胞迁移。了解胶原纤维网络的不同特性如何调节接触引导将进一步改善诊断活检图像的预后能力。胶原纤维密度的定量、活检的机械性能的测量、交联密度的替代和额外胶原结合伴侣的染色将使人们了解远离个体肿瘤的接触引导的效率。未来的工作将致力于在体内和小鼠肿瘤模型的活检中进行这些测量，并将这些生物物理和成分特性与肿瘤进展或预后相关联。