Project 2: Mechanochemical Mechanisms and Vulnerabilities of Individual and Collective Organ-Preferential Metastasis In Vivo

项目2：体内个体和集体器官优先转移的机械化学机制和脆弱性

• 批准号: 10490290
• 负责人: Peter Friedl
• 金额: $ 36.9万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10490290
• 关键词: Actomyosin; Address; Adherens Junction; Adhesions; Basement membrane; Blood Circulation; Blood Vessels; Breast Cancer Cell; CD44 gene; Cathepsins; Cell Cycle Arrest; Cell Death; Cell Nucleus; Cell Survival; Cell-Cell Adhesion; Cells; Cellular Stress; Chromatin; Chromatin Structure; Clinical; Coagulation Process; Computer Models; Cytometry; Cytoplasm; Data; Distant; Distant Metastasis; Down-Regulation; Endothelium; Engineering; Environment; Extravasation; Growth; Individual; Intercellular Junctions; Intervention; Kinetics; Lamin Type A; Liquid substance; Liver; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Mediating; Melanoma Cell; Metastatic Neoplasm to the Liver; Metastatic Skin Cancer; Microanatomy; Modeling; Molecular; Molecular Conformation; Molecular Target; Monitor; Movement; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Nuclear; Organ; Outcome; Pathway interactions; Peptide Hydrolases; Probability; Process; Regulation; Scheme; Secure; Site; Skin; Solid; Stress; Survival Rate; System; Testing; Tissue imaging; Tissues; Variant; Vascular remodeling; base; cancer cell; cell motility; coping; early onset; experience; fitness; in silico; in vivo; in vivo Model; intravital microscopy; live cell microscopy; mechanical properties; mouse model; multiphoton microscopy; neoplastic cell; novel; prevent; programs; response; shear stress; success; tissue stress; transcriptomics; triple-negative invasive breast carcinoma; vascular bed

Project 2: SUMMARY Organ colonization and survival of circulating tumor cells (CTCs) depends on a response program in tumor cells (TCs), termed mechano-adaptation, to cope with mechanical and molecular stresses on the cytoplasm and nucleus experienced during intravascular arrest and extravasation. The strength and duration of mechanical stress differs in vascular beds among organs, such as liver and skin, and further differs between individual-cell and collective organ colonization. Molecular systems implicated in the mechano-adaptation of CTCs include coordinated cell-cell adhesions, cytoskeletal contractility, protease systems and deformation or the nucleus, which cooperate to secure multistep movement into the secondary site and TC survival. We hypothesize that successful metastasis in vivo depends on an adaptive interplay between the mechanical and molecular intra- and perivascular stresses present at distant site and the coping ability of CTCs to overcome these stresses. By coordinated cell-cell adhesion, cytoskeletal contractility, deformation of the nucleus, and protease systems we predict that mechano-adaptation secures individual-cell and collective TC survival and further mediates lasting reprogramming towards growth or dormancy. Consequently, we anticipate that interfering with cell mechanical adaptation strategies will increase cell stress, support CTC death and diminish metastatic organ colonization. By combining intravital microscopy in mouse models, computational modeling (Core A) and transcriptomic and chromatin structure analyses (Core B), we will address the rate-limiting steps of single-cell and collective organ colonization of triple-negative breast cancer and melanoma cells to skin and liver. In Aim 1 we will examine the mechanisms of collective and single-cell organ colonization and metastatic outcomes, by interfering with adherens junctions (p120-catenin) and intravascular coagulation. In Aim 2, we will identify the rate-limiting steps of cytoskeletal and nuclear mechanics and the ability to remodel the vascular wall during single-cell and collective organ colonization. Targeted interference with CD44-mediated adhesion to perivascular substrate, actomyosin contractility, nuclear deformability by lamin A/C expression variation and the ability to reorganize the basement membrane will be performed. In Aim 3, we will identify the molecular responses underlying stress-induced mechano- adaptation and associated effects on nuclear chromatin conformation, using transcriptomic and ultrastructural analyses combined with computational modeling. Identified key pathways implicated in mediating mechano- adaptation and TC survival, cell cycle arrest (dormancy) and outgrowth will be inhibited by combined molecular interference to limit TC survival and both single-cell and collective metastasis. This project will deliver an integrated view on cell migration, molecular reprogramming, fate decisions, and reveal potential intervention points to enhance tumor cell elimination in transit.

项目2：概要 循环肿瘤细胞（CTC）的器官定植和存活取决于肿瘤中的应答程序。 细胞（TC），称为机械适应，以科普细胞质上的机械和分子应力 和核在血管内停搏和外渗过程中经历。的强度和持续时间 在器官（如肝脏和皮肤）之间的血管床中的机械应力不同，并且在器官之间的血管床中的机械应力也不同。 个体细胞和集体器官定植。分子系统参与的机械适应 CTC包括协调的细胞-细胞粘附、细胞骨架收缩性、蛋白酶系统和变形 或细胞核，它们合作以确保向次级部位的多步运动和TC存活。我们 假设体内成功转移依赖于机械性肿瘤之间的适应性相互作用， 和分子血管内和血管周围的压力存在于遥远的网站和应对能力的CTC， 克服这些压力。通过协调的细胞间粘附、细胞骨架收缩、 细胞核和蛋白酶系统，我们预测，机械适应确保个别细胞和集体TC 存活并进一步介导持久的重新编程以实现生长或休眠。因此我们 预期干扰细胞机械适应策略将增加细胞压力，支持CTC 死亡并减少转移性器官定植。通过在小鼠模型中结合活体显微镜， 计算建模（核心A）和转录组学和染色质结构分析（核心B），我们将 解决三阴性乳腺癌的单细胞和集体器官定植的限速步骤 黑色素瘤细胞转移到皮肤和肝脏在目标1中，我们将研究集体和单细胞的机制 通过干扰粘附连接（p120-连环蛋白）和 血管内凝血在目标2中，我们将确定细胞骨架和细胞核的限速步骤， 力学和在单细胞和集体器官定殖期间重塑血管壁的能力。 靶向干扰CD 44介导的血管周围基质粘附，肌动球蛋白收缩性， 核层蛋白A/C表达变化引起的核变形能力和重组基底膜的能力 将被执行。在目标3中，我们将确定应激诱导的机械性应激的分子反应。 利用转录组学和超微结构技术， 分析与计算建模相结合。确定了参与介导机械- 细胞周期阻滞（休眠）和生长将受到抑制， 分子干扰以限制TC存活以及单细胞和集体转移。该项目将 提供细胞迁移，分子重编程，命运决定的综合观点，并揭示潜力 干预点，以增强在运输中的肿瘤细胞消除。