Matrix Accumulation in the Metastatic Niche

转移生态位中的基质积累

基本信息

批准号：
10732790
负责人：
Sarah Libring
金额：
$ 8.59万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10732790
关键词：
3-Dimensional Apoptosis Architecture Atomic Force Microscopy Biomimetics Breast Cancer Cell Breathing Cancer Biology Cancer Cell Growth Cell Death Cell model Cell secretion Cells Cessation of life Clinical Communication Complex Coupled Desmoplastic Development Disease Doctor of Philosophy Educational process of instructing Endocrine Engineering Epithelium Exposure to Extracellular Matrix Fibroblasts Fibronectins Flow Cytometry Foundations Glycoproteins Goals Growth Lead Link Lung Malignant Neoplasms Malignant neoplasm of lung Mechanics Mentors Mesenchymal Metastatic Neoplasm to the Lung Metastatic breast cancer Methods Modeling Morbidity - disease rate Neoplasm Metastasis Nonmetastatic Output Pathway interactions Patients Periodicity Phenotype Positioning Attribute Postdoctoral Fellow Primary Neoplasm Production Proliferating Proteins Proteomics Research Research Personnel Role Signal Transduction Site Stretching Stromal Cells Structure of parenchyma of lung Survival Rate Testing Tissue Engineering Tissues Training Tumor Cell Migration Universities Vesicle Western Blotting Woman Work cancer cell cancer diagnosis cancer subtypes cell type conditioning defined contribution effective therapy experimental study extracellular extracellular vesicles improved in vivo insight interest lung volume malignant breast neoplasm mechanical force mechanical load mechanical properties mechanotransduction metabolic rate migration mortality neoplastic neoplastic cell novel paracrine phenotypic biomarker prevent single-cell RNA sequencing skills targeted treatment therapy development three dimensional cell culture three-dimensional modeling transmission process tumor microenvironment

项目摘要

Project Summary Breast cancer (BC) is the most frequently diagnosed cancer in women. In addition, metastatic BC has a 5-year survival rate of only 27% and metastases are associated with the vast majority of cancer-related deaths. Recent research has highlighted a complex dynamic between cancer cells and the tumor microenvironment as essential for the formation of macrometastases. Within this field, tissue stiffening through matrix accumulation and altered matrix organization were recently linked with sustained proliferation and increased migration of tumor cells. Elevated levels of the glycoprotein fibronectin (FN) have been correlated to poor patient survival in BC and are linked to enhanced seeding of disseminated tumor cells at metastatic sites. My previous work has indicated several mechanisms through which accumulated FN impacts the metastatic potential of BC cells. Foremost, I helped identify a transient increase in extracellular FN in the lungs, which peaked before overt metastasis, coupled with a non-transient increase in total lung volume. I further found that cyclic mechanical force acted as a suppressor of cancer cell growth in a biomimetic lung model, implicating the accumulation of extracellular matrix (ECM) as an attempt by the cancer cells to alter the mechanical properties of the lung tissue and resist entering dormancy. However, my results showed that BC cells could not organize FN into ECM independently. Instead, BC cells altered the accumulation and architecture of FN by conditioning resident fibroblasts through soluble factors and extracellular vesicles. I observed that the FN produced by conditioned fibroblasts varied not only based on the phenotype of the BC cell, but also from the method of conditioning which tested paracrine and endocrine signaling. These preliminary results indicate that unique subtypes of cancer associated fibroblasts (CAFs) may develop based on the BC cell conditioning mechanism, where unique subtypes may be associated with the specific needs of the various stages of the metastatic cascade. Therefore, Aim 1 of the proposed studies during my Ph.D. research will define the contribution of cyclic strain on BC cell phenotype and dormancy using our novel actuating platform. Aim 2, which I will undertake during my postdoctoral research, will seek to better define the varied roles of CAFs in metastatic progression through the development of a foundation of subtypes after conditioning with media, isolated extracellular vesicles, and contact from BC cancer cells, including metastatic and non-metastatic BC cells with epithelial and mesenchymal phenotypes. These findings will enable advanced interaction studies and promote the development of novel targets for fibroblasts, which may be a more consistent target than genetically unstable cancer cells and lead to more effective treatment. In addition, the proposed studies and training plan will expand my current tissue engineering skillset to include advanced understanding of mechanotransduction pathways and CAF formation as well as improve my communication, mentoring, and teaching. Together, these skills will place me as a competitive candidate for an independent principle investigator position in a research university at the intersection of cancer biology and engineering.

项目摘要乳腺癌（BC）是女性最常见的癌症。此外，转移性卑诗省有5年仅27％的生存率和转移与绝大多数与癌症相关的死亡有关。最近的研究强调了癌细胞与肿瘤微环境之间的复杂动态，这是必不可少的用于宏观变体的形成。在该领域，组织通过基质积累僵硬并改变基质组织最近与持续增殖和增加的肿瘤细胞迁移有关。糖蛋白纤连蛋白（FN）的水平升高与卑诗省的患者生存率不佳相关，并且与转移部位的散布肿瘤细胞增强的播种相关。我以前的工作已经表明积累FN会影响BC细胞的转移潜力的几种机制。最重要的是，我帮助确定肺部细胞外FN的短暂增加，该肺在明显转移之前达到峰值，再加上总肺部量的非变压增加。我进一步发现，环状机械力充当仿生肺模型中癌细胞生长的抑制剂，暗示细胞外的积累基质（ECM）作为癌细胞的尝试改变肺组织的机械性能并抵抗进入休眠。但是，我的结果表明，BC细胞无法独立地将FN组织到ECM中。相反，BC单元通过调节居民成纤维细胞通过调节FN的积累和结构可溶性因子和细胞外囊泡。我观察到由条件成纤维细胞产生的FN不变仅基于BC细胞的表型，还基于测试旁分泌和调节方法内分泌信号传导。这些初步结果表明，癌症相关的成纤维细胞的独特亚型（CAFS）可能会根据BC细胞调节机制开发，其中独特的亚型可能与之相关满足转移级联的各个阶段的特定需求。因此，拟议研究的目标1 在我的博士学位期间研究将定义循环应变对BC细胞表型和休眠的贡献我们的新颖的驱动平台。我将在博士后研究中进行的AIM 2将寻求更好通过开发亚型的基础来定义CAF在转移性进展中的各种作用用培养基调节后，分离的细胞外囊泡，并从卑诗省癌细胞接触带有上皮和间质表型的转移和非转移性BC细胞。这些发现将启用高级相互作用研究并促进成纤维细胞的新靶标的发展，这可能是更多一致的靶标比遗传不稳定的癌细胞，并导致更有效的治疗。另外，拟议的研究和培训计划将扩大我当前的组织工程技能，包括高级了解机械转导途径和CAF形成以及改善我的交流指导和教学。这些技能在一起将使我成为独立的竞争候选人癌症生物学与工程交集的研究大学的主要研究者职位。