Matrix Accumulation in the Metastatic Niche

转移生态位中的基质积累

• 批准号: 10475247
• 负责人: Sarah Libring
• 金额: $ 4.68万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475247
• 关键词: 3-Dimensional; Address; Apoptosis; Architecture; Atomic Force Microscopy; Biomimetics; Breast Cancer Cell; Breathing; Cancer Biology; Cancer Cell Growth; Cell Death; Cell model; Cells; Cessation of life; Clinical; Communication; Complex; Coupled; Desmoplastic; Development; Disease; Doctor of Philosophy; Educational process of instructing; Endocrine; Engineering; Epithelial; 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; Primary Neoplasm; Production; 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; base; 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 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

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)是女性最常见的确诊癌症。此外，转移性BC有5年的 只有27%的存活率和转移与绝大多数与癌症相关的死亡有关。近期 研究强调，癌细胞和肿瘤微环境之间的复杂动态是必不可少的 对于大转移瘤的形成。在这个能量场内，组织通过基质积累和改变而变硬 基质组织最近被认为与肿瘤细胞的持续增殖和迁移增加有关。 糖蛋白纤维连接蛋白(FN)水平的升高与BC和ARE患者的生存不良有关。 与在转移部位增强播散的肿瘤细胞播种有关。我之前的工作表明 积聚的FN影响BC细胞转移潜能的几种机制。首先，我 帮助确定了肺部细胞外FN的一过性增加，这种增加在明显转移之前达到顶峰， 伴随着总肺容量的非一过性增加。我进一步发现循环机械力起到了 在仿生肺模型中抑制癌细胞生长，暗示细胞外积聚 基质(ECM)是癌细胞试图改变肺组织的机械特性并抵抗 进入休眠状态。然而，我的结果显示BC细胞不能独立地将FN组织成ECM。 取而代之的是，BC细胞通过调节驻留成纤维细胞来改变FN的积累和结构 可溶性因子和胞外小泡。我观察到条件成纤维细胞产生的纤维连接蛋白没有变化。 不仅基于BC细胞的表型，而且还来自于检测旁分泌和 内分泌信号。这些初步结果表明，癌症相关成纤维细胞的独特亚型 (CAF)可能基于BC细胞条件作用机制，其中独特的亚型可能相关 随着转移性级联不同阶段的具体需求。因此，拟议研究的目标1 在我的博士期间，研究将确定周期性应变对BC细胞表型和休眠的贡献 我们的新型驱动平台。目标2，我将在我的博士后研究期间进行，将寻求更好的 通过亚型基础的建立，明确CAF在转移进展中的不同作用 在培养基预处理后，分离出细胞外小泡，并与BC癌细胞接触，包括 转移性和非转移性BC细胞，具有上皮和间质表型。这些发现将使 高级相互作用研究和促进成纤维细胞新靶点的开发，这可能是一种更 与基因不稳定的癌细胞相比，靶点一致，并导致更有效的治疗。此外， 拟议的研究和培训计划将扩展我目前的组织工程技能，包括高级 了解机械转导途径和CAF的形成，以及提高我的沟通能力， 辅导和教学。综合起来，这些技能将使我成为一名具有竞争力的独立候选人 位于癌症生物学和工程学交叉点的研究型大学的首席研究员职位。