Role of extracellular matrix malleability in mediating breast cancer cell invasion and migration

细胞外基质可塑性在介导乳腺癌细胞侵袭和迁移中的作用

• 批准号: 10314031
• 负责人: Ovijit Chaudhuri
• 金额: $ 36.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314031
• 关键词: Actins; Actomyosin; Basement membrane; Benign; Biocompatible Materials; Biophysical Process; Breast Cancer Cell; Carcinoma; Cells; Characteristics; Clinical Trials; Collagen; Disease; Ductal Carcinoma; Elasticity; Endothelium; Epithelial; Exhibits; Extracellular Matrix; Extravasation; Failure; Goals; Human; Integrin Binding; Integrins; Intervention; Invaded; Knowledge; Lead; Lesion; Ligands; Liquid substance; Malignant - descriptor; Malignant Epithelial Cell; Matrix Metalloproteinase Inhibitor; Measures; Mechanics; Mediating; Mesenchymal; Mission; Modeling; Molecular; Molecular Target; Morphology; Nanoporous; Nature; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Peptide Hydrolases; Pharmacology; Physiological; Process; Proliferating; Public Health; Research; Resistance; Role; Structure; Testing; Tissues; United States National Institutes of Health; Viscosity; Work; breast cancer progression; breast lesion; cancer cell; cancer type; cell motility; cell type; density; disability; infiltrating duct carcinoma; innovation; malignant breast neoplasm; mammary epithelium; mechanical properties; migration; mortality; novel; novel diagnostics; novel therapeutic intervention; polymerization; prevent; three dimensional cell culture; viscoelasticity

Ductal carcinoma is the most common form of breast cancer and progresses to Invasive Ductal Carcinoma (IDC) when the carcinoma invades through the basement membrane (BM) into the stromal tissue. Invasion is a key step in ductal carcinoma progression that is associated with an increased likelihood for metastasis, the most deadly aspect of breast cancer. During metastasis, cancer cells must also invade BM during intravasation and extravasation. Cancer cells are thought to utilize proteases to degrade the BM during invasion of the BM using specialized structures known as invadopodia. Known modes of protease-independent invasion and migration, involving cells squeezing through pores in the ECM, would be inhibited by the nanoporous nature of the BM. However, physiological ECM is viscoelastic, exhibiting some characteristics of viscous fluids, and cellular forces can induce flow and permanent deformation of the matrix. In other words, viscoelastic ECM is malleable, and cell generated forces may expand pores, providing a mechanism for cells to mechanically remodel the ECM and physically clear a path for migration, independent of proteases. While malleability is related to matrix viscosity, it is distinct from matrix elasticity. Interestingly, malignant breast lesions have been found to exhibit a greater degree of viscosity than benign lesions. Importantly, the concept of malleability might be relevant to protease-dependent migration as well, as the action of proteases may be to make the matrix more malleable. The specific hypothesis to be tested in this application is that malleability is a key physical parameter of the BM that mediates protease-dependent and protease-independent cancer cell invasion and migration. This hypothesis is supported by preliminary studies finding that cancer cells can invade and migrate through nanoporous matrices that contain BM ligands with intermediate or high-malleability in a protease- independent manner, utilizing invadopodial like protrusions to initiate invasion, but are unable to invade and migrate through matrices with low malleability. This hypothesis will be tested by pursuing the following three specific aims: (1) Fabricate materials for 3D cell culture with independently tunable malleability that present ligands and stiffness relevant to the BM of mammary epithelium; (2) Determine how ECM malleability regulates invadopodial protrusions; and (3)! Identify molecular and biophysical mechanisms underlying protease- independent migration through ECMs with different levels of malleability. This approach is innovative because of its focus on understanding the role of malleability in mediating protease-independent and -dependent invasion and migration, as malleability is a physical characteristic of ECM, related to matrix viscosity but distinct from elasticity or density, which has been largely ignored in studies to date. The proposed research is significant because it will reveal the role of ECM malleability in mediating both protease-dependent and protease-independent invasion and migration by breast cancer cells, potentially uncovering previously un- described modes of invasion or migration.

导管癌是乳腺癌最常见的形式，并且发展为侵入性导管癌 （IDC）当癌通过基底膜（BM）侵入基质组织时。入侵是 导管癌进展的关键步骤与转移的可能性增加有关 乳腺癌最致命的方面。在转移期间，癌细胞还必须在插入期间侵入BM 和奢侈。癌细胞被认为利用蛋白酶在侵袭BM期间降解BM 使用称为Invadopodia的专业结构。蛋白酶无关入侵的已知模式和 迁移，涉及细胞通过ECM中的毛孔挤压的迁移将受到纳米孔的抑制 BM。但是，生理ECM是粘弹性的，表现出粘性液体的某些特征，并且 细胞力可以诱导基质的流动和永久变形。换句话说，粘弹性ECM是 可延展，细胞产生的力可能会膨胀孔，为细胞提供机制的机制 重塑ECM并物理清除迁移的路径，与蛋白酶无关。而锻造性是 与基质粘度有关，它与基质弹性不同。有趣的是，恶性乳房病变已经 发现比良性病变表现出更大程度的粘度。重要的是，延展性的概念可能 与蛋白酶依赖性迁移有关，因为蛋白酶的作用可能是使矩阵 更可延展。在本应用程序中要测试的具体假设是锻造性是关键的物理 BM的参数介导蛋白酶依赖性和蛋白酶独立的癌细胞侵袭和 迁移。初步研究发现，癌细胞可以入侵和迁移，这一假设得到了支持 通过纳米孔矩阵，其中包含蛋白酶中具有中间或高糖化性的BM配体 独立的方式，利用侵袭像突起来启动入侵，但无法入侵和 通过较低的矩阵迁移。该假设将通过追求以下三个来检验 具体目的：（1）用独立可调的锻造性制造3D细胞培养物的材料 配体和刚度与乳腺上皮的BM相关； （2）确定如何调节ECM锻造性 侵袭性突起； （3）！识别蛋白酶基础的分子和生物物理机制 独立迁移通过具有不同水平的可锻造性的ECM迁移。这种方法是创新的，因为 它专注于理解延展性在介导蛋白酶无关和依赖性中的作用 入侵和迁移，因为锻造性是ECM的物理特征，与基质粘度有关，但 与弹性或密度不同，迄今为止的研究在很大程度上被忽略了。拟议的研究是 意义重大，因为它会揭示ECM延展性在介导蛋白酶依赖性和 乳腺癌细胞不依赖蛋白酶的侵袭和迁移，可能会发现以前没有 描述了入侵或迁移的模式。