Core1: Computational

计算核心(核心A)：摘要 指导和解释体外实验(方案1)和体内实验(方案2)，并提供物理基础 对于机械压力下转录模式的变化(核心B)，该核心将采用 一系列跨越各种长度和时间范围的计算工具。其中包括单元格模型 黏附，细胞骨架功能，细胞-基质相互作用和核力学的三维多尺度模型 转导和染色质组织。这套建模工具将揭示 细胞和核在渗出和迁移过程中的变形，对液体和液体的机械适应 固体应激、血管内和血管外生态位特性和细胞死亡 集群式CTC。值得注意的是，3D基因组组织的建模将使我们能够阐明 细胞机制、染色质组织和转录之间的关系，从而提供了关于如何 机械应激对转移过程中基因表达的调控及可逆性和持续性的鉴定 染色质变形与细胞存活或死亡有关。 癌细胞单独或集体入侵，但支配它们在组织中定居的策略的因素 而它们在血管内应激和血管外渗中存活的能力也鲜为人知。虽然联轴器 细胞收缩、核力学转导以及与细胞外基质和血管壁的黏附相互作用 已知影响细胞黏附和运动，但这种相互作用对细胞存活的影响尚未得到严格的证实 调查过了。为了阐明参与这种调控的物理机制，我们开发了3D化学- 描述粘连、细胞骨架和骨骼之间的三向反馈的力学模型 原子核。该模型显示了细胞和细胞外交界处产生的局部拉应力。 环境调节细胞核的性质，包括核形态、层蛋白A/C、组蛋白水平 YAP/TAZ的脱乙酰化和核质穿梭，进而控制空间染色质组织， 基因表达和细胞生存和应对机械压力的能力。建立在这些基础上 工具，这个项目的具体目标是： 目的1.预测血管壁龛内血管血流对肿瘤细胞停滞和存活的影响。 ·目标2.模拟个人/集体渗出的机械力化学/分子机制 CTC。 ·目标3.预测染色质组织和转录模式变化的影响 血管内应激和血管外渗对移行肿瘤存活和生长的影响 单元格

Computational Core (Core A): SUMMARY To guide and interpret the in vitro (Project 1) and in vivo experiments (Project 2) and to provide a physical basis for changes in transcriptional patterns in response to mechanical stresses (Core B), this core will employ an array of computational tools spanning a wide range of length and time scales. These include models for cell adhesion, cytoskeletal function, cell-matrix interactions and 3D multiscale models for nuclear mechano- transduction and chromatin organization. This suite of modeling tools will reveal non-linear interactions between cell and nuclear deformation during of extravasation and migration, mechano-adaptation in response to fluid and solid stresses, intravascular and extravascular niche properties and cell death for individual compared to clustered CTCs. Significantly, modelling of 3D genome organization will allow us to elucidate the relationship between the mechanics of the cell, chromatin organization, and transcription, thus providing new insights on how mechanical stresses regulate gene expression during metastasis, and identification of reversible and persisting chromatin deformation associates with cell survival or death. Cancer cells invade individually or collectively, but the factors that govern their strategies to colonize the tissue and their ability to survive intravascular stress and extravasation are poorly understood. While the coupling between cell contractility, nuclear mechanotransduction, and adhesive interactions with the ECM and vessel wall is known to affect cell adhesion and motility, the effects of this interplay on cell survival has yet to be rigorously investigated. To elucidate the physical mechanisms involved in such regulation, we developed 3D chemo- mechanical models to describe the three-way feedback between the adhesions, the cytoskeleton, and the nucleus. The model shows local tensile stresses generated at the interface of the cell and the extracellular environment regulate the properties of the nucleus, including nuclear morphology, levels of lamin A/C, histone deacetylation and nucleo-cytoplasmic shuttling of YAP/TAZ, which in turn govern spatial chromatin organization, gene expression and the ability of the cells to survive and cope with the mechanical stresses. Building on these tools, the specific aims of this project are: · Aim 1. Predict the role of vascular flow on tumor cell arrest and survival in the intravascular niche. · Aim 2. Model the mechanochemical/molecular mechanisms of individual/collective extravasation of CTCs. · Aim 3. Predict the influence of alterations in chromatin organization and transcriptional patterns induced by intravascular stress and extravasation on the survival and growth of migrating tumor cells