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: 10443246
• 负责人: Ovijit Chaudhuri
• 金额: $ 34.78万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10443246
• 关键词: Actins; Actomyosin; Award; Basement membrane; Benign; Biocompatible Materials; Biophysical Process; Breast Cancer Cell; Bulla; Carcinoma; Cell Cycle Progression; Cells; Characteristics; Clinical Trials; Collagen; Collagen Type I; Disease; Ductal Carcinoma; Elasticity; Endothelium; Epithelium; Exhibits; Extracellular Matrix; Extravasation; Failure; Filopodia; Goals; Human; Individual; Integrin Binding; Integrins; Intervention; Invaded; Knowledge; Lesion; Ligands; Malignant - descriptor; Malignant Epithelial Cell; Matrix Metalloproteinase Inhibitor; Measures; Mechanics; Mediating; Mesenchymal; Mission; Mitotic; Modeling; Molecular; Molecular Target; Morphology; Nanoporous; Nature; Neoplasm Metastasis; Noninfiltrating Intraductal Carcinoma; Peptide Hydrolases; Phase; Physiological; Polymers; Process; Proliferating; Public Health; Research; Resistance; Role; Testing; Tissues; United States National Institutes of Health; Viscosity; Work; breast cancer progression; breast lesion; cancer cell; cancer type; cell motility; cell type; crosslink; density; disability; epigenome; infiltrating duct carcinoma; innovation; malignant breast neoplasm; malignant phenotype; mammary epithelium; mechanical properties; migration; mortality; novel; novel diagnostics; novel therapeutic intervention; pharmacologic; polymerization; prevent; three dimensional cell culture; tumor progression; 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. The overall goal of our work is to determine how matrix mechanical plasticity (malleability) regulates breast cancer invasion and migration. In the initial 5-year phase of this R37 award, we found that breast cancer tissue is mechanically plastic, and that individual breast cancer cells can migrate through nanoporous matrices independent of proteases using invadopodia if the matrix exhibits sufficient matrix mechanical plasticity. We also found that increased covalent crosslinking of the matrix or increased stiffness inhibits invadopodia formation, and that cancer cells can utilize filopodia to migrate along soft basement-membrane-like substrates if the substrate is sufficiently viscoelastic or malleable. We have also pursued related lines on inquiry, finding that extracellular matrix viscoelasticity regulates cell-cycle progression, that cancer cells generate force in order to undergo mitotic elongation and divide in confining type-1 collagen rich matrices, that increased stiffness regulates breast cancer progression through a YAP-independent mechanism, and that increased stiffness induces broad changes in the epigenome that functionally mediate a stiffness-induced malignant phenotype in mammary epithelium. While our initial studies on the role of malleability in invasion focused on single cell invasion, initial invasion of the BM during cancer progression is thought to be collective in nature, involving the coordinated activity of multiple cells. The specific hypothesis to be tested in this R37 extension application is that matrix mechanical plasticity (malleability) is a key physical parameter mediates collective invasion of the BM and subsequent migration through the type-1 collagen rich stromal matrix during cancer progression. This hypothesis will be tested by pursuing the following two specific aims: (1) Determine how basement membrane mechanical plasticity (malleability) mediates collective cell invasion; (2) Determine how mechanical plasticity (malleability) of type-1 collagen rich matrices mediates collective migration of breast cancer cells. 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. This work is also innovative in its focus on collective invasion of the basement membrane instead of single cell invasion. The proposed research is significant because it will reveal the role of ECM malleability in mediating both protease-dependent and protease-independent collective invasion and migration by breast cancer cells, potentially uncovering previously un-described modes of invasion or migration.

导管癌是乳腺癌中最常见的一种，进展为浸润性导管癌(IDC)。 当癌通过基底膜(BM)侵入间质组织时。入侵是关键 与转移可能性增加相关的导管癌进展中的一步，最 乳腺癌的致命方面。在转移过程中，癌细胞还必须在血管内和 渗出。我们工作的总体目标是确定基质的机械塑性(延展性) 调节乳腺癌的侵袭和转移。在这个R37奖项的最初5年阶段，我们发现乳房 癌症组织是机械可塑性的，单个乳腺癌细胞可以通过纳米孔迁移 如果基质表现出足够的机械可塑性，则使用不依赖于蛋白酶的基质。 我们还发现，增加基质的共价交联度或增加硬度可以抑制内翻足 癌细胞可以利用丝状基底物沿着柔软的基底膜样底物迁移，如果 基材具有足够的粘弹性或延展性。我们也进行了相关的调查，发现 细胞外基质粘弹性调节细胞周期进程，癌细胞产生力量以 经历有丝分裂的延长，并在限制的类型-1型胶原丰富的基质，这增加了硬度 通过一种不依赖YAP的机制调节乳腺癌的进展，这种僵硬程度的增加 在表观基因组中诱导广泛的变化，在功能上介导僵直诱导的恶性表型 乳腺上皮细胞。虽然我们最初对延展性在侵袭中的作用的研究集中在单细胞侵袭上， 在癌症进展过程中，骨髓最初的侵袭被认为是集体性的，涉及协调的 多个细胞的活动。在此R37扩展应用程序中要测试特定假设是矩阵 机械塑性(延展性)是调节BM集体侵袭的关键物理参数 在癌症进展过程中，随后通过富含1型胶原的基质基质进行迁移。这一假设 将通过追求以下两个具体目标进行测试：(1)确定基底膜如何机械 可塑性(延展性)调节集体细胞入侵；(2)决定机械可塑性(延展性)如何 富含1型胶原的基质介导乳腺癌细胞的集体迁移。这种方法是创新的。 因为它侧重于理解延展性在调节蛋白酶非依赖性和依赖性中的作用 侵袭和迁移，因为延展性是ECM的一个物理特性，与基质粘度有关，但不同 从弹性或密度来看，这在很大程度上被研究忽视了。这项工作还具有创新性，其 重点是基底膜的集体侵袭，而不是单个细胞的侵袭。拟议的研究 具有重要意义，因为它将揭示ECM延展性在调节蛋白水解酶依赖和 乳癌细胞非依赖于蛋白水解酶的集体侵袭和迁移 未描述的入侵或迁徙方式。