Project 3: Physical and Metabolic Constraints of Cancer Cell Invasion

项目摘要-项目3 项目3将调查癌细胞侵袭的物理和代谢限制。癌细胞侵袭 从原发肿瘤到周围组织是转移级联的关键一步，这是 造成绝大多数癌症死亡的原因。侵袭的癌细胞可以使用许多不同的 这一进程的“迁移模式”。由于细胞可以在这些模式之间动态切换，治疗尝试 靶向特定的迁移机制在临床上的成功有限。获得更好的理解 控制不同迁徙模式之间切换的物理和生物机制可能 为更有力的治疗干预提供新的线索，以减少或消除转移。一个重要的问题 以前没有研究过的因素是单个细胞的代谢状态如何决定它们的 迁移方式和转移扩散。当癌细胞穿过紧密的间质和代谢产物时- 在体内的贫穷地区，他们面临着巨大的身体和新陈代谢挑战。我们认为侵袭性癌症 细胞必须花费大量的能量来穿透这样的环境，并采用最小化的迁移模式 新陈代谢成本。癌细胞的新陈代谢也会影响细胞的结构和组成 生物合成途径，可以改变细胞表面结构和核变形能力，从而 在狭小的空间中促进迁徙。拟议的研究将利用项目团队的补充 在细胞迁移、亚细胞生物力学、活体显微镜和代谢途径以及 干扰。目标1阐述了物理微环境以及细胞和细胞之间的粘连/摩擦 细胞外环境决定了不同类型细胞迁移过程中的能量消耗。目标2将 研究细胞固有的物理因素，特别是核的变形性和物理特性 细胞表面的性质，调节代谢成本和迁移效率在生理上相关 环境。它将进一步确定癌细胞中的代谢重新编程如何影响这些细胞 机械性能，从而调节迁移效率。目标3将研究的可塑性 癌细胞迁移对不同的生理和代谢挑战以及对药物的反应 干扰。每个目标的实验工作都将得到癌细胞新陈代谢模型的补充。 以及与微环境的物理相互作用，目的是预测治疗结果 代谢干预，并确定应对适应性反应的战略。项目3将与两者进行交互 核心。组织微制造核心将为迁移分析提供生物样本和平台； 生物物理学和新陈代谢成像核心协助代谢分析和成像平台。项目1 和2将为CELL的全面计算建模框架提供数据和见解 迁移中的新陈代谢；项目2还将提供用于功能评估的肿瘤微囊。

Project Summary – Project 3 Project 3 will investigate the physical and metabolic constraints of cancer cell invasion. Cancer cell invasion from the primary tumor into surrounding tissues is a crucial step of the metastatic cascade, which is responsible for the vast majority of all cancer deaths. Invading cancer cells can use a number of different `migration modes' for this process. As cells can dynamically switch between these modes, therapeutic attempts to target specific migration mechanisms have had limited clinical success. Gaining an improved understanding of the physical and biological mechanisms that govern the toggling between different migration modes could provide new clues for more robust therapeutic interference to reduce or eliminate metastasis. One important factor that has not been examined previously is how the metabolic status of individual cells can determine their migration mode and metastatic spreading. As cancer cells pass through tight interstitial spaces and metabolite- poor regions in vivo, they face substantial physical and metabolic challenges. We propose that invading cancer cells must expend significant energy to penetrate such environments and adopt migration modes that minimize metabolic cost. Cancer cell metabolism can also impact cellular structure and composition by fueling biosynthetic pathways, which could alter cell surface architecture and nuclear deformability, and thereby promote migration through tight spaces. The proposed research will utilize the project team's complementary expertise in cell migration, subcellular biomechanics, intravital microscopy, and metabolic pathways and interference. Aim 1 addresses how the physical microenvironment and adhesion/friction between the cell and the extracellular environment determine energy consumption during different types of cell migration. Aim 2 will investigate how physical factors intrinsic to the cell, particularly nuclear deformability and the physical properties of the cell surface, modulate metabolic cost and migration efficiency in physiologically relevant environments. It will further determine how metabolic reprogramming in cancer cells affects these cellular mechanical properties and thereby modulates migration efficiency. Aim 3 will investigate the plasticity of cancer cell migration, both in response to varying physical and metabolic challenges and to pharmacological interference. The experimental work in each aim will be complemented by modeling of cancer cell metabolism and physical interaction with the microenvironment, with the objective to predict outcomes of therapeutic metabolic interventions and to identify strategies to counter adaptive responses. Project 3 will interact with both Cores. The Tissue Microfabrication Core will provide biological samples and platforms for migration assays; the Biophysics & Metabolic Imaging Core assists with metabolic analysis and imaging platforms. Projects 1 and 2 will contribute data and insights for a comprehensive computational modeling framework of cell metabolism in migration; Project 2 will additionally provide tumor microvesicles for functional evaluation.