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

• 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
• 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

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.

转移占癌症相关死亡的绝大多数，但其潜在机制是 不完全理解。在肿瘤进展过程中，肿瘤微环境发生广泛重塑 发生并促进转移。特别是胶原蛋白的线性化，胶原蛋白是最丰富的细胞外物质之一 肿瘤中的基质（ECM）蛋白被认为是侵袭性乳腺癌的标志，并且与 预后不良。在细胞水平上，线性化胶原束促进肿瘤细胞侵袭和 通过提供肿瘤细胞可以轻松迁移的轨道来实现转移。细胞产生的机械张力 有人提出有助于胶原蛋白重塑，但仍不清楚这是否是唯一的 胶原蛋白线性化的建立机制或其他机制是否也发挥着重要作用 在此过程中的角色。我们最近的研究表明，癌细胞会分泌能够使胶原蛋白线性化的因子 独立于细胞产生的机械力。具体来说，我们发现肿瘤细胞分泌因子 WISP1 (CCN4) 促进胶原线性化、肿瘤细胞侵袭和转移。然而，蜂窝和 WISP1 线性化胶原蛋白并促进转移的分子机制仍不完全 明白了。为了揭示这些机制，我们将 1）定义转移级联的具体步骤， 受 WISP1 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) 测试阻断 WISP1 功能的治疗方式 并防止转移。这将通过对乳腺癌进展进行详细分析来实现 和小鼠模型中的转移和体外侵袭测定。我们研究的核心还在于使用 扫描电子显微镜和活体多光子荧光和二次谐波产生 显微镜观察体外和体内 ECM 结构的变化。在全球范围内，这些研究将阐明 胶原纤维线性化的基本机制并测试创新的治疗方法以限制 通过使胶原结构正常化来转移。