Matrix Accumulation in the Metastatic Niche

转移生态位中的基质积累

• 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
• 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

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）是女性中最常见的癌症。此外，转移性BC具有5年的 只有27%的存活率和转移与绝大多数癌症相关的死亡有关。最近 研究强调了癌细胞和肿瘤微环境之间的复杂动态 大转移的形成。在这个领域内，组织硬化通过基质积累和改变 基质组织最近与肿瘤细胞的持续增殖和增加的迁移有关。 糖蛋白纤连蛋白（FN）水平升高与BC患者生存率差相关， 这与在转移部位增强播散的肿瘤细胞的接种有关。我之前的研究表明 积累的FN通过几种机制影响BC细胞的转移潜能。首先，我 有助于确定肺中细胞外FN的短暂增加，在明显转移之前达到峰值， 并伴有肺总容量的非暂时性增加。我进一步发现循环机械力 在仿生肺模型中的癌细胞生长抑制剂，涉及细胞外 细胞外基质（ECM）作为癌细胞试图改变肺组织的机械性质并抵抗肿瘤细胞的侵袭的一种手段。 进入休眠期然而，我的研究结果表明，BC细胞不能组织FN到ECM独立。 相反，BC细胞通过调节常驻成纤维细胞改变了FN的积累和结构， 可溶性因子和细胞外囊泡。我观察到条件成纤维细胞产生的FN变化不大， 不仅基于BC细胞的表型，而且还来自测试旁分泌的调节方法， 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细胞调节机制发展，其中可能与独特的亚型相关。 与转移级联的各个阶段的特定需要相结合。因此，拟议研究的目标1 在我读博士的时候研究将确定循环应变对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 通过亚型基础的发展，确定CAF在转移进展中的不同作用 在用培养基、分离的细胞外囊泡和BC癌细胞接触后，包括 具有上皮和间充质表型的转移性和非转移性BC细胞。这些发现将使 先进的相互作用研究，并促进新的目标成纤维细胞的发展，这可能是一个更 与遗传不稳定的癌细胞相比，它具有一致的靶点，并导致更有效的治疗。此外该 拟议的研究和培训计划将扩大我目前的组织工程技能，包括先进的 了解机械传导途径和CAF形成，以及提高我的沟通， 指导和教学。总之，这些技能将使我成为一个有竞争力的候选人， 在一所研究型大学担任癌症生物学和工程学交叉学科的首席研究员。