Coordination Funds

协调基金

• 批准号: 530849418
• 负责人: Professor Dr. Ingolf Sack
• 金额: --
• 依托单位: Klinik für Radiologie (mit dem Bereich Kinderradiologie) (CCM)
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/530849418?language=en
• 关键词: Coordination; Funds

The mechanical niche of cancer emerges from the collective behavior of cells, which is guided by their physical interactions with extracellular matrix, stromal cells and lymphatic and blood vessels. These mechanosensory signals result in unique material properties not found in inanimate matter and are closely linked to the emergent states of cancer cells in correlation with their aggressiveness and metastatic potential. Multiscale-multifrequency magnetic resonance elastography (mMRE) can quantitatively map material properties of tumors in vivo including tissue stiffness, friction, and fluidity. Here, we propose an interdisciplinary research unit for the study of cancer mechanics to unveil, for the first time, the mechano-physical cascade of carcinogenesis in vivo, to decipher the physical signals that transform dormant tumors into aggressive cancers, to mechanistically understand the properties of tumor niches that promote tumor development, invasive growth, and cancer recurrence after therapy, and to develop diagnostic imaging markers based on mMRE. Covering different length scales, we will sensitize micromechanical test methods and mMRE to disrupted tissue homeostasis, matrix remodeling, and non-equilibrium cellular interactions that collectively shape the mechanical microenvironment in which tumors grow and proliferate. We will combine state-of-the-art biotechnology approaches in organoid cultures and recellularized tissue scaffolds with animal tumor models, micromechanical test methods, metabolic modeling, and multiparametric, quantitative imaging including mMRE in tissue samples and patients to study the multiscale mechanical properties of the cancerogenic niche from microscopic to macroscopic length scales. This approach will allow us to thoroughly test our main hypothesis that in vivo mMRE i) is sensitive to solid-fluid mechanical property changes associated with tumor development, ii) is specific to collective cellular behavior underlying malignant transformation, and iii) predicts the formation of solid stress in carcinogenic niches. Our research plan evolves around three pillars that cover the micro-, meso- and macroscopic ranges of tumor properties. Each pillar combines innovative multiparametric imaging techniques including micromechanical tests and clinical mMRE as well as analyses of transcriptomics, proteomics, cell and nucleus shape and histopathology in both ex vivo specimens and in vivo tissues. We will systematically analyze and combine these multiscale data by viscoelastic modeling of the fundamental properties of cancers across entities and individual tumor stages with the perspective of advancing noninvasive diagnostic imaging by mMRE towards risk stratification of tumor development, aggressiveness, and recurrence after treatment. Ultimately, focusing on in vivo soft tissue mechanics, this research unit is going to tackle the long-standing yet unresolved question of the origin of cancer from the physics perspective.

癌症的机械生态位源于细胞的集体行为，这是由细胞与细胞外基质、基质细胞、淋巴管和血管的物理相互作用引导的。这些机械感觉信号产生无生命物质中未发现的独特材料特性，并且与癌细胞的侵袭性和转移潜力的出现状态密切相关。多尺度多频磁共振弹性成像（mMRE）可以定量绘制体内肿瘤的材料特性，包括组织硬度、摩擦力和流动性。在这里，我们提出了一个跨学科研究单位来研究癌症力学，首次揭示体内致癌作用的机械物理级联，破译将休眠肿瘤转变为侵袭性癌症的物理信号，从机制上了解促进肿瘤发展、侵袭性生长和治疗后癌症复发的肿瘤微环境的特性，并开发基于诊断成像标记物 在 mMRE 上。涵盖不同的长度尺度，我们将使微机械测试方法和 mMRE 对破坏的组织稳态、基质重塑和非平衡细胞相互作用敏感，这些相互作用共同塑造了肿瘤生长和增殖的机械微环境。我们将把类器官培养和再细胞化组织支架中最先进的生物技术方法与动物肿瘤模型、微观机械测试方法、代谢模型和多参数定量成像（包括组织样本和患者中的 mMRE）相结合，研究致癌生态位从微观到宏观长度尺度的多尺度机械特性。这种方法将使我们能够彻底检验我们的主要假设，即体内 mMRE i) 对与肿瘤发展相关的固液机械特性变化敏感，ii) 对恶性转化下的集体细胞行为具有特异性，iii) 预测致癌生态位中固体应力的形成。我们的研究计划围绕三个支柱展开，涵盖肿瘤特性的微观、中观和宏观范围。每个支柱都结合了创新的多参数成像技术，包括显微机械测试和临床 mMRE，以及离体标本和体内组织的转录组学、蛋白质组学、细胞和细胞核形状以及组织病理学分析。我们将通过对跨实体和个体肿瘤阶段的癌症基本特性进行粘弹性建模，系统地分析和组合这些多尺度数据，并着眼于通过 mMRE 推进无创诊断成像，以实现肿瘤发展、侵袭性和治疗后复发的风险分层。最终，该研究单位将重点关注体内软组织力学，将从物理学角度解决癌症起源这一长期存在但尚未解决的问题。