Core1: Computational

计算核心（核心 A）：总结 指导和解释体外（项目 1）和体内实验（项目 2）并提供物理基础 对于响应机械应力（核心 B）的转录模式的变化，该核心将采用 一系列跨越各种长度和时间尺度的计算工具。这些包括细胞模型 粘附、细胞骨架功能、细胞-基质相互作用和核力学的 3D 多尺度模型 转导和染色质组织。这套建模工具将揭示之间的非线性相互作用 外渗和迁移过程中的细胞和核变形、响应流体的机械适应和 与个体相比，固体应力、血管内和血管外生态位特性以及细胞死亡 聚集的 CTC。重要的是，3D 基因组组织的建模将使我们能够阐明这种关系 细胞机制、染色质组织和转录之间的关系，从而提供关于如何 机械应力调节转移过程中的基因表达，并识别可逆性和持久性 染色质变形与细胞存活或死亡相关。 癌细胞单独或集体入侵，但控制其定殖组织策略的因素 人们对它们抵抗血管内压力和外渗的能力知之甚少。而联轴器 细胞收缩性、核力转导以及与 ECM 和血管壁的粘附相互作用之间的关系 已知会影响细胞粘附和运动，但这种相互作用对细胞存活的影响尚未得到严格证实 调查了。为了阐明这种调节所涉及的物理机制，我们开发了 3D 化学 力学模型来描述粘附、细胞骨架和细胞之间的三向反馈 核。该模型显示了细胞和细胞外界面处产生的局部拉应力 环境调节细胞核的特性，包括核形态、核纤层蛋白 A/C 水平、组蛋白 YAP/TAZ 的脱乙酰化和核质穿梭，进而控制空间染色质组织， 基因表达以及细胞生存和应对机械应力的能力。在此基础上 工具，该项目的具体目标是： · 目标 1. 预测血管血流对血管内微环境中肿瘤细胞停滞和存活的作用。 · 目标 2. 模拟个体/集体外渗的机械化学/分子机制 CTC 的数量。 · 目标 3. 预测染色质组织和转录模式改变的影响 血管内应激和外渗对迁移性肿瘤存活和生长的影响 细胞

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