Targeting invadopodia-related mechanisms of cancer cell invasion and metastasis

针对癌细胞侵袭和转移的侵袭伪足相关机制

• 批准号: 10613490
• 负责人: Bojana Gligorijevic
• 金额: $ 37.23万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-18 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613490
• 关键词: 3-Dimensional; Acceleration; Actins; Adhesions; Affect; Biological Assay; Blood Vessels; Breast Cancer Cell; Cell Communication; Cell Cycle; Cell Cycle Progression; Cell Cycle Regulation; Cells; Cellular Structures; Cessation of life; Cyclin-Dependent Kinases; EMS1 gene; Equilibrium; Extracellular Matrix; Extracellular Matrix Degradation; Extracellular Matrix Proteins; Feedback; Fluorescence; Frequencies; G1 Arrest; G1 Phase; Goals; Image; Image Analysis; In Vitro; Integrins; Intervention; Invaded; Investigation; Label; Link; Locomotion; MMP14 gene; Machine Learning; Metalloproteases; Methodology; Methods; Microscopy; Modeling; Modification; Neoplasm Metastasis; Outcome; Patients; Peptide Hydrolases; Phase; Phenotype; Phosphotransferases; Prevention; Proliferating; Proteins; Resolution; Role; Sampling; Scaffolding Protein; Speed; Structural Protein; System; Testing; Time; Visualization; Work; breast imaging; cancer cell; cell motility; chemotherapy; crosslink; cyclin-dependent kinase inhibitor 1B; gain of function; imaging modality; in vivo; inhibitor; insight; intravital imaging; intravital microscopy; kinase inhibitor; knock-down; loss of function; malignant breast neoplasm; mathematical model; migration; neoplastic cell; novel; novel strategies; prevent; real-time images; receptor; serial imaging; temporal measurement; tool

Metastasis causes >90% of breast cancer-related deaths. Tumor cell structures that have been hypothesized as necessary for metastasis are invadopodia, protrusions rich in structural proteins (e.g. Tks5), adhesion proteins (e.g. integrin β1) and proteases (e.g. MT1-MMP), known to degrade the extracellular matrix (ECM) proteins. A novel, real-time imaging methodology that allows investigation of the in vivo metastatic role of invadopodia found that cells which assemble invadopodia move at “Slow” speeds and are seen in perivascular niches. Outside of perivascular niches, “Fast” motile cells, which do not assemble invadopodia were observed. This method also showed that invadopodia are essential for intravasation in vivo. Preliminary work has begun to determine which aspects of the Slow phenotype allow invadopodia assembly. Use of novel mathematical models, in vitro microscopy and novel computational image analysis demonstrates that whereas the Fast cells continuously locomote, the Slow cells are in either of two oscillating states: i. Invadopodia state, in which a cell is sessile while it degrades surrounding ECM; ii. Locomotion state, similar to a Fast cell. The oscillation dynamics appear to depend on interactions between the ECM and its receptor integrin β1. Importantly, the Invadopodia, but not Locomotion state, is limited to G1 phase of the cell cycle. Release from G1-arrest amplifies invadopodia, implying that G1-arresting therapies may promote metastasis. This project will identify the mechanisms unique to the Invadopodia state compared to cells that only proliferate or locomote, with the idea of targeting the Invadopodia state. Overall Hypothesis: the Invadopodia state, which is essential for metastasis, requires a pause in both cell locomotion and cell cycle progression. The initiation and termination of the Invadopodia state are controlled by the interaction between the ECM, invadopodia components integrin β1 and Tks5, as well as the cyclin-dependent kinase inhibitor p27 (expressed during G1). Aim 1. Determine the role of the cell cycle in regulating the Invadopodia state. Using real-time imaging of cell cycle and invadopodia markers in vitro and in vivo, this Aim tests the hypothesis that cyclin- dependent kinases and corresponding inhibitors regulate the Invadopodia state, but not the Locomotion. Aim 2. Determine the role of ECM-cancer cell interactions in regulating the oscillations between Invadopodia and Locomotion states. This Aim will provide a strategy based on in vivo modification of integrin β1 activity on how to turn Invadopodia state ”off” towards metastatic prevention. Significance. Invadopodia is suggested as a new candidate target for metastatic prevention. The use of cell cycle inhibitors in patients with invadopodia may be accelerating metastatic dissemination. The long- term goal is to predict and prevent metastasis using invadopodia.

与乳腺癌相关的死亡中，有90%是由转移引起的。肿瘤细胞结构已经被 假设转移所必需的是内向突起，即富含结构蛋白的突起(例如 β)、黏附蛋白(如整合素TK5)和蛋白酶(如MT1-MMP1)，已知可降解 细胞外基质(ECM)蛋白。 一种新的实时成像方法，允许研究在体内的转移作用 Invadoodia发现，组装inadoodia的细胞移动速度很慢，可以在 血管周围的壁龛。在血管周围的壁龛外，“快速”可移动的细胞不会聚集在一起。 都观察到了。这一方法还表明，体内血管内皮细胞的侵入是必不可少的。 初步工作已经开始确定慢的表型的哪些方面允许不定形 集合。使用新的数学模型、体外显微镜和新的计算图像分析 证明快速细胞持续运动，而慢细胞在两个细胞中的任何一个 振荡状态：i.不定形状态，在此状态下，细胞在细胞外基质周围降解的同时处于静止状态； 运动状态，类似于快速细胞。振荡动力学似乎依赖于 细胞外基质及其受体整合素β1。重要的是，不动足而不是运动状态仅限于 细胞周期的G1期。从G1期停滞中释放会放大内向，意味着G1期停滞 治疗可能会促进肿瘤转移。这个项目将确定发明百科全书独有的机制。 与仅增殖或移动的细胞相比，状态是以失足动物状态为目标的。 总体假设：对于转移至关重要的内陷状态，需要一个 暂停细胞运动和细胞周期进程。法律程序的启动和终止 介体状态由ECM、介体组件之间的相互作用控制 整合素β1和TKS5，以及细胞周期蛋白依赖性激酶抑制因子p27(在G1期表达)。 目的1.确定细胞周期在调节不定足状态中的作用。使用实时 在体外和体内对细胞周期和跨足类标志物的成像，这一目的验证了细胞周期蛋白- 依赖的激酶和相应的抑制物调节内翻足的状态，但不调节运动。 目的2.确定ECM-癌细胞相互作用在调节细胞与癌细胞之间的振荡中的作用 失足状态和运动状态。这一目标将提供一种基于体内修饰的策略 整合素β-1活性关于如何关闭失禁状态以防止转移。 意义重大。因此，我们建议将其作为预防肿瘤转移的新的候选靶点。对.的使用 内翻足病患者的细胞周期抑制物可能加速转移扩散。长的- 学期的目标是使用Inadoodia来预测和预防转移。

项目成果

Pharmacodynamic Studies of Fluorescent Diamond Carriers of Doxorubicin in Liver Cancer Cells and Colorectal Cancer Organoids.

肝癌细胞和大肠癌器官中阿霉素的荧光钻石载体的药效学研究。

• DOI: 10.2147/nsa.s321725
• 发表时间: 2021
• 期刊: Nanotechnology, science and applications
• 作者: Firestein R;Marcinkiewicz C;Nie L;Chua HK;Velazquez Quesada I;Torelli M;Sternberg M;Gligorijevic B;Shenderova O;Schirhagl R;Feuerstein GZ
• 通讯作者: Feuerstein GZ

Proteolytic and mechanical remodeling of the extracellular matrix by invadopodia in cancer.

• DOI: 10.1088/1478-3975/aca0d8
• 发表时间: 2022-11-21
• 期刊: Physical biology
• 影响因子: 2