The role of DDR2 in the breast cancer microenvironment

DDR2在乳腺癌微环境中的作用

• 批准号: 9272729
• 负责人: Samantha Van Hove Bayer
• 金额: $ 3.07万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9272729
• 关键词: Affect; Architecture; Benign; Biochemical; Biology; Biophysics; Breast; Breast Cancer Cell; Breast Cancer Model; Breast cancer metastasis; Cancer Control; Cancer Etiology; Cell Transplants; Cell surface; Cellular biology; Cessation of life; Characteristics; Collagen; Collagen Fiber; Data; Defect; Development; Disease; Disease Progression; Distant Metastasis; Environment; Epithelial; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fiber; Fibrillar Collagen; Fibroblasts; Genetic; Genetic Models; Growth; Human; Implant; In Vitro; Incidence; Knockout Mice; Lead; Ligands; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mesenchymal; Metastatic Neoplasm to the Lung; Metastatic to; Modeling; Molecular; Mus; Neoplasm Metastasis; Outcome; Polyomavirus; Primary Neoplasm; Process; Production; Prognostic Factor; Proteins; Radial; Receptor Protein-Tyrosine Kinases; Research; Risk; Role; Signal Pathway; Signal Transduction; Stromal Cells; Stromal Neoplasm; Structure; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Tumor Cell Invasion; Tumor Cell Migration; Tumor Pathology; Wild Type Mouse; Woman; Work; cancer diagnosis; cancer therapy; cell motility; cell type; crosslink; density; discoidin domain receptor 2; experimental study; implantation; in vivo; knock-down; malignant breast neoplasm; neoplastic cell; permissiveness; prognostic; prognostic value; public health relevance; recombinase-mediated cassette exchange; targeted treatment; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Breast cancer is the most commonly diagnosed cancer and second most leading cause of cancer related deaths in women. Importantly, women are much more likely to die from metastatic progression of disease rather than primary tumors. Tumor cells are surrounded and supported by the tumor microenvironment, and current research indicates that stromal cells and extracellular matrix molecules influence and promote metastatic progression. Features of the tumor microenvironment such as alignment of collagen fibers and density influence cell motility, invasion, and subsequent metastasis. It has been shown that increased stromal collagen, increased collagen crosslinking, stiffness of matrices, and increased radial alignment of collagen fibers near tumors is correlated with metastasis and is prognostic for worse outcomes, however the mechanism behind how this change in the stroma occurs is not known. The Longmore lab recently demonstrated that the cell surface molecule DDR2 (Discoidin Domain Receptor 2) positively regulates breast cancer metastasis. When DDR2 depleted tumor cells were implanted into the breast of syngeneic wild-type mice, the associated stroma was less aligned and fewer metastases were observed, indicating a role for DDR2 in stromal remodeling in tumor cells. This experiment did not rule out a role for the matrix producing cancer associated fibroblasts (CAFs), and, importantly, DDR2 ubiquitous null mice have decreased tumor desmoplasia and metastasis in a PyMT genetic model of breast cancer. When DDR2 positive tumor cells were implanted into the breast of DDR2 global null mice, nearly zero metastases were observed, indicating that the activity of DDR2 in the host microenvironment is required for metastasis. Further, preliminary data from conditional deletion of DDR2 in breast tumor stromal cells using FSP1-Cre show a significant decrease in lung metastasis. Finally, in ex vivo preliminary experiments, DDR2 depleted CAFs produce a disorganized ECM, indicating that DDR2 is required in CAFs for matrix alignment. The specific cellular mechanisms and signaling events downstream of DDR2 activation which regulate stromal organization remain unknown and will be studied in the aims of this proposal. The role of DDR2 in tumor cells and CAFs will be parsed out and whether DDR2 affects production of matrix, remodeling of existing matrix, or both will be determined. The downstream signaling pathways of DDR2 that effect the change in stroma alignment will be elucidated, and this project further aims to study the in vivo effect of breast CAF DDR2 on distant metastasis in mice. These aims will be tested in ex vivo models of matrix production and remodeling and in vivo analyses in mice of tumor pathology, tumor stromal signature, and lung metastasis. These advances will serve to further illustrate how changes in the tumor microenvironment can promote metastasis and identify potential targets for therapeutic intervention.

 描述（由申请人提供）：乳腺癌是最常诊断的癌症，也是女性癌症相关死亡的第二大原因。重要的是，女性更有可能死于疾病的转移性进展，而不是原发性肿瘤。肿瘤细胞被肿瘤微环境包围和支持，目前的研究表明，基质细胞和细胞外基质分子影响和促进转移进展。肿瘤微环境的特征，如胶原纤维的排列和密度影响细胞运动、侵袭和随后的转移。已经表明，基质胶原蛋白增加、胶原蛋白交联增加、基质硬度增加和肿瘤附近胶原纤维径向排列增加与转移相关，并且是更差结果的预后，然而基质中这种变化如何发生的机制尚不清楚。Longmore实验室最近证明，细胞表面分子DDR2（盘状结构域受体2）正调控乳腺癌转移。当将DDR2耗尽的肿瘤细胞植入同基因野生型小鼠的乳房中时，观察到相关的基质较少对齐并且较少转移，表明DDR2在肿瘤细胞中的基质重塑中的作用。该实验没有排除产生癌症相关成纤维细胞（CAF）的基质的作用，并且重要的是，DDR2遍在缺失小鼠在乳腺癌的PyMT遗传模型中具有减少的肿瘤结缔组织增生和转移。当将DDR2阳性肿瘤细胞植入DDR2全局无效小鼠的乳房中时，观察到几乎为零的转移，表明宿主微环境中DDR2的活性是转移所必需的。此外，使用FSP 1-Cre在乳腺肿瘤基质细胞中条件性缺失DDR2的初步数据显示肺转移显著减少。最后，在离体初步实验中，DDR2耗尽的CAF产生无序的ECM，表明CAF中需要DDR2进行基质比对。调节基质组织的DDR2激活下游的特定细胞机制和信号事件仍然未知，将在本提案的目的中进行研究。DDR2在肿瘤细胞和CAF中的作用将被解析出来，并且DDR2是否影响基质的产生、现有基质的重塑或两者都将被确定。DDR2影响间质排列变化的下游信号通路将被阐明，本项目进一步旨在研究乳腺CAF DDR2对小鼠远处转移的体内作用。这些目标将在基质产生和重塑的离体模型中进行测试，并在小鼠中进行肿瘤病理学、肿瘤基质特征和肺转移的体内分析。这些进展将有助于进一步说明肿瘤微环境的变化如何促进转移，并确定治疗干预的潜在靶点。