Collagen remodeling and tumor progression

胶原重塑和肿瘤进展

• 批准号: 8617811
• 负责人: VALERIE MARIE WEAVER
• 金额: $ 35.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-07 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8617811
• 关键词: 1-Phosphatidylinositol 3-Kinase; 2-Oxoglutarate 5-Dioxygenase Procollagen-Lysine; Actomyosin; Address; Antibodies; Archives; Automobile Driving; Behavior; Biological; Biological Assay; Biopsy; Breast; Breast Epithelial Cells; Cancer Etiology; Cells; Cellular biology; Cessation of life; Chemotaxis; Cleaved cell; Clinical Trials; Collagen; Collagen Fibril; Data; Desmoplastic; Detection; Development; Dimensions; Dominant-Negative Mutation; Engineering; Enzymes; Epidermal Growth Factor Receptor; Epithelium; Extracellular Matrix; Family; Fibrosis; Focal Adhesions; Future; Genetic; Goals; Growth; Growth Factor; Growth Factor Receptors; Human; Image; In Vitro; Incidence; Individual; Integrins; Knowledge; Lesion; Life; Link; Malignant - descriptor; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Mammary gland; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mechanics; Mediating; Metastatic to; Methods; Modality; Molecular; Monitor; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Oncogenes; Organoids; PDZ protein; PTEN gene; Palpable; Pathogenesis; Play; Prevention; Property; Protein-Lysine 6-Oxidase; Proteins; Receptor Signaling; Regulation; Reporting; Research; Risk; Role; Signal Transduction; Structure; Testing; Tissues; Transgenic Mice; Tumor Cell Invasion; Tumor Suppressor Proteins; Woman; Women' s Health; Work; breast density; breast lesion; cell growth; cell motility; cellular imaging; clinically relevant; crosslink; gain of function; genetic manipulation; high risk; human BCAR1 protein; improved; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; interstitial; loss of function; malignant breast neoplasm; malignant phenotype; mammary epithelium; migration; mouse model; mutant; neoplastic; patient population; receptor; research study; response; time use; treatment response; tumor; tumor progression

DESCRIPTION (provided by applicant): The global objective of this research is to clarify the relevance of interstitial collagen remodeling in breast tumor progression. Neoplastic progression in the breast is accompanied by a desmoplastic response which is characterized by significant remodeling of interstitial collagen and is associated with a progressive stiffening of the tissue. Progressively transformed mammary epithelial cells (MECs) become sensitized to extracellular matrix (ECM) stiffness, implying that it is the dialogue between a dynamically evolving microenvironment and a progressively aberrant mammary epithelium that is key for neoplastic progression. ECM-degrading matrix metalloproteinases (MMPs) expressed in the stroma cleave interstitial collagen and contribute to the pathogenesis of tumor progression, and elevated MMP expression is predictive of neoplastic progression of human breast lesions. Yet clinical trials with MMP inhibitors failed, suggesting other parameters of ECM remodeling modulate tumor behavior. The lysyl oxidase and lysyl hydroxylase family of enzymes are also expressed in the stroma where they cross-link collagen fibrils to enhance the mechanical integrity of the tissue. These enzymes are also elevated in tumors and contribute to tissue fibrosis. Indeed, the levels of collagen and matrix proteins that enhance ECM stiffness are elevated in women with mammographically dense breasts, who are at higher risk for breast cancer. These data emphasize the importance of collagen cross-linking as well as MMP-degradation to breast cancer progression. Nevertheless, our understanding of the role of collagen cross linking to tumor progression is limited. The goal for this proposal is to dissect, in molecular and cell biological detail, how collagen cross-linking, which stiffens the ECM, contributes to breast cancer progression to a malignant phenotype. Given that tumor progression is mediated through elevated levels/activity of oncogenes and reduced levels/activity of tumor suppressors we suggest that collagen remodeling/stiffening influences tumor progression by modifying the levels/activity of key oncogenes or tumor suppressors. Consistently, we found that ECM cross-linking and stiffness enhance integrin and growth factor receptor (GFR) signaling and regulate levels of the tumor suppressor PTEN. Accordingly, we hypothesize that collagen cross-linking stiffens the tissue to promote breast transformation by enhancing integrin-GFR signaling and reducing the levels of tumor suppressors such as PTEN. The project will take an interdisciplinary approach, using engineering methods to measure and manipulate ECM materials properties and topology in culture and in vivo, together with molecular cell biology methods and genetic mouse models to investigate whether collagen remodeling and cross-linking promote tumor progression by stiffening the breast tissue to enhance integrin and GFR signaling and/or compromising PTEN expression/function. Archived and fresh biopsies of pre-neoplastic breast tissue from women at high and low risk for collagen abundance and structure will establish clinical relevance. We will exploit live cell imaging of organotypic cultures in two- and three-dimensions in natural and synthetic matrices with modified cross-linking, stiffness and topology and will use mice that have been pharmacologically or antibody-modified to have altered collagen structures to interrogate whether collagen cross-linking and stiffness influence MEC motility and invasion by enhancing PI3 kinase signaling to promote chemotaxis and durotaxis. These experiments will give insight into how collagen abundance and cross-linking contribute to the progression of pre-neoplastic lesions to invasive breast cancer. This knowledge will assist in the development of approaches to identify and characterize molecular mechanisms driving breast tumor progression to invasion. The studies will lay the groundwork for future studies aimed at clarifying the role of the tissue ECM in metastasis and treatment response. The work will eventually help to achieve the long-term goal of finding cures for breast cancer and is directly pertinent for other tumor types.

描述(申请人提供)：这项研究的总体目标是阐明间质胶原重构与乳腺肿瘤进展的相关性。乳腺肿瘤的进展伴随着促结缔组织反应，其特征是间质胶原的显著重塑，并与组织的进行性硬化有关。渐进性转化的乳腺上皮细胞(MECs)对细胞外基质(ECM)硬度敏感，这意味着动态演变的微环境与渐进性异常的乳腺上皮之间的对话是肿瘤进展的关键。细胞外基质降解基质金属蛋白酶(MMPs)在基质中裂解间质胶原蛋白，参与肿瘤的发生发展，高表达的MMPs可预测乳腺肿瘤的进展。然而，使用基质金属蛋白酶抑制剂的临床试验失败了，这表明ECM重塑的其他参数调节了肿瘤的行为。赖氨酰氧化酶和赖氨酸羟基酶家族也在基质中表达，在那里它们交联胶原纤维以增强组织的机械完整性。这些酶在肿瘤中也会升高，并导致组织纤维化。事实上，在乳房X光检查致密的女性中，提高细胞外基质硬度的胶原蛋白和基质蛋白水平会升高，她们患乳腺癌的风险更高。这些数据强调了胶原蛋白的交联性和基质金属蛋白酶的降解对乳腺癌进展的重要性。然而，我们对胶原交联物在肿瘤进展中的作用的了解是有限的。这项建议的目标是从分子和细胞生物学细节上剖析胶原交联物如何使细胞外基质变硬，从而促进乳腺癌进展为恶性表型。鉴于肿瘤进展是通过癌基因水平/活性升高和肿瘤抑制因子水平/活性降低来调节的，我们认为胶原重构/僵化通过改变关键癌基因或肿瘤抑制因子的水平/活性来影响肿瘤进展。我们一致地发现，细胞外基质的交联和僵硬增强了整合素和生长因子受体(GFR)信号，并调节了肿瘤抑制因子PTEN的水平。因此，我们假设，胶原交联物通过增强整合素-GFR信号和降低肿瘤抑制因子如PTEN的水平，使组织变硬，从而促进乳房转化。该项目将采取跨学科的方法，使用工程方法来测量和操纵ECM材料在培养和体内的性质和拓扑结构，并结合分子细胞生物学方法和遗传小鼠模型来研究胶原重塑和交联剂是否通过使乳房组织僵硬来增强整合素和GFR信号和/或损害PTEN的表达/功能来促进肿瘤进展。来自胶原丰度和结构高风险和低风险妇女的癌前病变组织的存档和新鲜活组织检查将建立临床相关性。我们将在天然和合成基质中利用二维和三维器官型培养的活细胞成像，通过修改交联度、硬度和拓扑结构，并将使用经过药物或抗体修饰的改变胶原结构的小鼠来询问胶原交联度和硬度是否通过增强PI3激酶信号来促进趋化和趋化作用，从而影响MEC的运动和侵袭。这些实验将深入了解胶原丰富和交联物如何有助于癌前病变向浸润性乳腺癌的进展。这一知识将有助于开发方法来识别和表征推动乳腺肿瘤进展到侵袭的分子机制。这些研究将为未来旨在阐明组织ECM在转移和治疗反应中的作用的研究奠定基础。这项工作最终将有助于实现找到乳腺癌治疗方法的长期目标，并与其他类型的肿瘤直接相关。

项目成果

Fibronectin rescues estrogen receptor α from lysosomal degradation in breast cancer cells.

• DOI: 10.1083/jcb.201703037
• 发表时间: 2018-08-06
• 期刊: The Journal of cell biology
• 作者: Sampayo RG;Toscani AM;Rubashkin MG;Thi K;Masullo LA;Violi IL;Lakins JN;Cáceres A;Hines WC;Coluccio Leskow F;Stefani FD;Chialvo DR;Bissell MJ;Weaver VM;Simian M
• 通讯作者: Simian M