The Role of Basement Membrane Biomechanics in Cancer Cell Invasion

基底膜生物力学在癌细胞侵袭中的作用

基本信息

批准号：
8712407
负责人：
Aron Parekh
金额：
$ 11.5万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712407
关键词：
Affect Animal Model Automobile Driving Basement membrane Behavior Biological Biomechanics Bladder Body part Breast Cancer Biology Carcinoma Cells Characteristics Chemicals Clinical Collagen Fiber Complex Connective Tissue Deposition Desmoplastic Development Plans Doctor of Medicine Doctor of Philosophy Electron Microscopy Epithelial Extracellular Matrix Extracellular Matrix Degradation Focal Adhesion Kinase 1 Foundations Funding Future Goals Imaging Techniques Immunofluorescence Immunologic Immunohistochemistry In Vitro Invaded Knowledge Laboratories Lead Left Link MMP14 gene Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary gland Mechanics Medical Membrane Mentors Modeling Molecular Biology Neoplasm Metastasis Outcome Patients Penetration Peptide Hydrolases Phenotype Play Positioning Attribute Primary Neoplasm Process Property Proteins Research Personnel Research Proposals Role Signal Transduction Simulate Site Stretching Stromal Invasion Structure Survival Rate Swelling Techniques Testing Time Tissues Training Western Blotting Work cancer cell career career development cell motility cell transformation crosslink density experience human MMP14 protein in vitro Model in vivo inhibitor/antagonist insight malignant breast neoplasm malignant phenotype multidisciplinary neoplastic cell novel novel therapeutics prevent public health relevance research study response scaffold skills tumor tumor growth tumor microenvironment tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The objective of this application is to develop the career of Dr. Aron Parekh as an independent researcher in the field of cancer invasion. The career development plan created by the PI and his mentor Alissa M. Weaver, M.D., Ph.D., and co-mentor Vito Quaranta, M.D., combines both the didactic and laboratory training required to build Dr. Parekh's biological knowledge and skills. The ultimate goal of the training period is to combine the PI's expertise in mechanics and mechanobiology with the mentors' expertise in molecular biology and advanced imaging techniques to equip Dr. Parekh to become a multidisciplinary researcher focused on the mechanisms of cancer cell mechanobiology. The proposed training opportunity would provide the PI protected time to gain valuable knowledge and experience in acquiring these skills to position him for a successful career in cancer invasion. The research proposal, described below, serves as the foundation of this five year career development plan and of future funding proposals. Long-term clinical outcomes are dependent on whether carcinoma cells leave the primary tumor site by migrating and invading through epithelial and adjacent stromal tissues. Cancer aggressiveness has been linked to tissue density and rigidity both in vivo and in vitro. Our laboratory has shown that mechanosensing of rigid substrates is correlated to increased extracellular matrix (ECM) degradation due to elevated activity of invadopodia, the cytoskeletal structures thought to be critical for proteolytic invasion. Therefore, these results suggest that mechanical factors such as tensile forces play an important role in driving a malignant phenotype. However, the link between biomechanics and the invasion of actual tissues remains inconclusive due to the lack of in vitro models that mimic true tissue properties, particularly those of the epithelial basement membrane (BM) and stroma. In vivo, mechanical forces generated by tumor cell packing and the desmoplastic stroma lead to increased rigidity or tension in the mammary gland and mechanical loading of the local ECM including the BM and adjoining stroma. Therefore, mechanical forces exerted on the local ECM may play an important role in regulating the invasive phenotype, but currently no studies have tested the role of ECM biomechanics under conditions that simulate the tumor microenvironment. The goal is to determine the role of these external forces in regulating cancer cell migration and invasion through the ECM. To achieve this goal, three specific aims are proposed. In Specific Aim 1, the chemical, physical, and mechanical properties of the ECM scaffold urinary bladder matrix-BM (UBM-BM) will be characterized to establish this material as a physiologically relevant in vitro ECM model. In Specific Aim 2, the hypothesis that BM tension activates a malignant phenotype that facilitates invasion will be tested by examining the penetration of UBM-BM under tension by invasive cancer cells. In contrast, Specific Aim 3 will test whether invasion through the adjacent stromal tissue occurs independent of proteolytic degradation and/or mechanosensing by utilizing the connective tissue component of UBM-BM as a model for the stroma. Dr. Parekh anticipates that these studies will yield important insight into the mechanism responsible for mechanically activating cancer cells to penetrate the BM and stroma and could open the door for novel therapeutic strategies that interfere with these processes.

描述（由申请人提供）：本申请的目的是发展Aron Parekh博士作为癌症入侵领域的独立研究人员的职业。 PI和他的导师Alissa M. Weaver，医学博士和M.D. Co-Enctor Vito Quaranta制定的职业发展计划结合了建立Parekh博士的生物学知识和技能所需的教学和实验室培训。培训期的最终目标是将PI在力学和机械生物学方面的专业知识与指导者在分子生物学和高级成像技术方面的专业知识相结合，以使Parekh博士成为一名跨多学科研究人员，专注于癌细胞机械生物学的机制。拟议的培训机会将为PI受保护的时间，以获得宝贵的知识和经验，以获取这些技能，以将他定位为成功的癌症入侵职业。下面描述的研究建议是这项五年职业发展计划和未来资助建议的基础。长期临床结果取决于癌细胞是否通过通过上皮和邻近的基质组织迁移和入侵来离开原发性肿瘤部位。癌症的侵略性与体内和体外的组织密度和僵化有关。我们的实验室表明，刚性底物的机械连感应与由于Invadopodia活性升高而导致的细胞外基质（ECM）降解相关，这是细胞骨架结构被认为对蛋白水解侵袭至关重要。因此，这些结果表明，诸如拉伸力等机械因素在驱动恶性表型中起着重要作用。然而，由于缺乏模仿真实组织特性的体外模型，尤其是上皮地下膜（BM）和基质的体外模型，生物力学与实际组织的入侵之间的联系仍然尚无定论。在体内，由肿瘤细胞堆积产生的机械力和脱落基质会导致乳腺中的刚度或张力提高，以及包括BM和毗邻基质（包括BM）的局部ECM的机械负载。因此，施加在本地ECM上的机械力可能在调节侵入性表型中起重要作用，但是目前尚无研究在模拟肿瘤微环境的条件下测试ECM生物力学的作用。目的是确定这些外力在调节癌细胞迁移和通过ECM侵袭的作用。为了实现这一目标，提出了三个具体目标。在特定目标1中，ECM支架泌尿膀胱基质-BM（UBM-BM）的化学，物理和机械性能将被表征为在体外ECM模型中建立该材料。在特定的目标2中，BM张力激活了促进入侵的恶性表型的假设将通过检查在侵入性癌细胞下张力下的UBM-BM渗透来测试。相反，特定的目标3将通过利用UBM-BM的结缔组织成分作为基质的模型来测试通过相邻基质组织的侵袭是否与蛋白水解降解和/或机械感应无关。 Parekh博士预计，这些研究将对负责机械激活癌细胞穿透BM和基质的机制产生重要的见解，并可以为干扰这些过程的新型治疗策略打开大门。