Regulation of collagen linearization during cancer progression and metastasis

癌症进展和转移过程中胶原蛋白线性化的调节

基本信息

批准号：
10600821
负责人：
Myriam Labelle
金额：
$ 40.24万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-20 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600821
关键词：
Affect Amino Acids Architecture Binding Biological Assay Blood Blood Platelets Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Bypass C-terminal Cell secretion Cells Cessation of life Circulation Clinical Collagen Collagen Fiber Collagen Type I Confocal Microscopy Cysteine Data Deposition Disease Event Extracellular Matrix Extracellular Matrix Proteins Extravasation Face Fibroblasts Fluorescence Gene Expression Generations Human Implant In Vitro Injections Invaded Knockout Mice Malignant Neoplasms Mammary Neoplasms Mechanics Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Microscopy Modality Modeling Molecular Mus Neoplasm Metastasis Pathogenicity Play Positioning Attribute Primary Neoplasm Process Prognosis Recombinants Regulation Role Scanning Electron Microscopy Signal Transduction Site Stream Structure of parenchyma of lung Tail Tertiary Protein Structure Testing Therapeutic Tumor Cell Invasion Tumor Promotion Veins Visualization WISP1 gene aggressive breast cancer breast cancer progression cancer cell clinical prognostic in vivo innovation knock-down knowledgebase malignant breast neoplasm mechanical force migration mouse model multi-photon mutant neoplastic cell novel overexpression patient derived xenograft model prevent prognostic value second harmonic therapeutic evaluation time use tumor tumor microenvironment tumor progression

项目摘要

Metastasis accounts for the vast majority of cancer-related deaths but its underlying mechanisms are incompletely understood. During tumor progression extensive remodeling of the tumor microenvironment occurs and facilitates metastasis. In particular, linearization of collagen, one of the most abundant extracellular matrix (ECM) proteins in tumors, is recognized as a hallmark of aggressive breast cancers and is associated with poor prognosis. At the cellular level, bundles of linearized collagen facilitate tumor cell invasion and metastasis by providing tracks on which tumor cells can easily migrate. Cell-generated mechanical tension has been proposed to contribute to collagen remodeling, but it remained unknown whether this is the sole mechanism by which collagen linearization is established or whether other mechanisms also play prominent roles in this process. Our recent studies revealed that cancer cells secrete factors that can linearize collagen independently of cell-generated mechanical forces. Specifically, we found that the tumor cell-secreted factor WISP1 (CCN4) promotes collagen linearization, tumor cell invasion and metastasis. However, the cellular and molecular mechanisms by which WISP1 linearizes collagen and promote metastasis remain incompletely understood. To uncover these mechanisms we will 1) define the specific steps of the metastatic cascade that are impacted by WISP1, 2) determine the molecular mechanisms by which WISP1 regulates collagen linearization and promotes tumor cell invasion, and 3) test therapeutic modalities to block WISP1’s function and prevent metastasis. This will be achieved by performing detailed analyses of breast cancer progression and metastasis in mouse models and in vitro invasion assays. Central to our studies is also the use of scanning electron microscopy and intravital multiphoton fluorescence and second harmonic generation microscopy to visualize alterations in ECM architecture in vitro and in vivo. Globally, these studies will elucidate fundamental mechanisms of collagen fiber linearization and test innovative therapeutic approaches to limit metastasis by normalizing collagen architecture.

转移占绝大多数与癌症相关的死亡，但其潜在机制是不完全理解。在肿瘤进展过程中，肿瘤微环境进行了广泛的重塑发生并促进转移。特别是，胶原蛋白的线性化，最丰富的细胞外之一肿瘤中的基质（ECM）蛋白被认为是侵略性乳腺癌的标志，并且与预后不良。在细胞水平上，线性化胶原蛋白有助于肿瘤细胞的侵袭和通过提供肿瘤细胞可以轻松迁移的轨道来转移。细胞生成的机械张力具有我们被提议为胶原蛋白的重塑做出贡献，但尚不清楚这是否是唯一的建立胶原蛋白线性化的机制或其他机制是否也发挥着突出在此过程中的角色。我们最近的研究表明，癌细胞的秘密因素可以线性化胶原蛋白独立于细胞生成的机械力。具体而言，我们发现肿瘤细胞分泌因子 WISP1（CCN4）促进胶原蛋白线性化，肿瘤细胞侵袭和转移。但是，细胞和 WISP1线性化胶原蛋白和促进转移的分子机制保持不完全理解齿。要揭示这些机制，我们将1）定义转移级联的特定步骤受WISP1的影响，2）确定WISP1调节胶原蛋白的分子机制线性化并促进肿瘤细胞侵袭，3）测试治疗方式阻止Wisp1的功能并防止转移。这将通过对乳腺癌进展的详细分析来实现和小鼠模型和体外入侵测定法中的转移。我们研究的中心也是扫描电子显微镜和浸润性多光子荧光和第二次谐波产生显微镜检查体外和体内ECM体系结构的改变。在全球，这些研究将阐明胶原纤维线性化和测试创新治疗方法的基本机制以限制转移通过标准化胶原蛋白结构。