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.

转移造成90％的乳腺癌相关死亡。肿瘤细胞结构 据称是转移所必需的，是富含结构蛋白的蛋白质（例如， TKS5），粘合蛋白（例如整联蛋白β1）和蛋白质（例如MT1-MMP），已知可以降解 细胞外基质（ECM）蛋白。 一种新颖的实时成像方法，允许研究体内转移性作用 Invadopodia发现组装Invadodia的细胞以“缓慢”的速度移动并在 血管周围壁ni。在血管周期壁ches之外，“快速”基序细胞，这些细胞不会组装不足的Invadopodia 观察到。该方法还表明，Invadodia对于体内侵入至关重要。 初步工作已经开始确定慢速表型的哪些方面允许Invadopodia 集会。使用新型数学模型，体外显微镜和新型计算图像分析 证明快速细胞继续发挥作用，而慢单元在两个中的任何一个 振荡状态：i。 Invadopodia状态，其中一个细胞是无柄的，而ECM周围会降解； ii。 运动状态，类似于快速单元。振荡动力学似乎取决于 ECM及其受体整联蛋白β1。重要的是，侵袭性疾病（但不是运动状态）仅限于 细胞周期的G1相。从G1暂停放大器Invadopodia释放，这意味着G1在 疗法可能会促进转移。该项目将确定Invadopodia独有的机制 状态与仅增殖或发球的细胞与靶向侵袭性状态的想法相比。 总体假设：对转移至关重要的Invadopodia状态需要一个 在细胞运动和细胞周期进程中暂停。主动和终止 Invadopodia状态受ECM，Invadopodia组件之间的相互作用控制 整联蛋白β1和TKS5，以及细胞周期蛋白依赖性激酶抑制剂p27（在G1中表达）。 AIM 1。确定细胞周期在调查Invadopodia状态中的作用。使用实时 在体外和体内的细胞周期和侵袭性标志物的成像，该目标检验了细胞周期蛋白的假设 依赖性激酶和相应的抑制剂调节侵袭性状态，但不调节运动。 AIM 2。确定ECM-Canter细胞相互作用在调节振荡之间的作用 Invadopodia和运动状态。此目标将基于体内修改的策略 整联蛋白β1的活性对如何将Invadopodia状态“ OFF”转向转移性预防。 意义。有人建议将Invadopodia作为预防转移性的新候选靶标。使用 患有Invadopodia患者的细胞周期抑制剂可能正在加速转移性传播。长期 术语目标是使用Invadopodia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.

• 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