Coordination Funds

癌症的机械生态位产生于细胞的集体行为，这是由它们与细胞外基质、基质细胞、淋巴和血管的物理相互作用所引导的。这些机械感觉信号导致了在无生命物质中没有发现的独特物质特性，并且与癌细胞的突发性状态密切相关，与它们的侵袭性和转移潜力相关。多尺度-多频率磁共振弹性成像（mMRE）可以定量绘制肿瘤体内的材料特性，包括组织刚度、摩擦和流动性。在此，我们建议建立一个跨学科的癌症力学研究单位，首次揭示体内癌变的机械-物理级联，破译将休眠肿瘤转化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壁龛特性，并开发基于mMRE的诊断成像标记。在不同的长度尺度上，我们将使微力学测试方法和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。我们将结合最先进的生物技术方法在类器官培养和再细胞化组织支架与动物肿瘤模型，微力学测试方法，代谢建模，多参数，定量成像，包括组织样本和患者的mMRE，以研究从微观到宏观长度尺度的致癌生态位的多尺度力学特性。这种方法将使我们能够彻底验证我们的主要假设，即体内mMRE 1)对与肿瘤发展相关的固体-流体力学特性变化敏感，2)特异性于恶性转化的集体细胞行为，以及3)预测致癌生态位中固体应激的形成。我们的研究计划围绕三个支柱发展，涵盖肿瘤特性的微观，中观和宏观范围。每个支柱结合了创新的多参数成像技术，包括微力学测试和临床mMRE以及转录组学，蛋白质组学，细胞和细胞核形状以及离体标本和体内组织的组织病理学分析。我们将系统地分析和结合这些多尺度数据，通过跨实体和个体肿瘤分期的癌症基本特性的粘弹性建模，并从推进mMRE无创诊断成像的角度对肿瘤发展、侵袭性和治疗后复发进行风险分层。最终，该研究小组将专注于体内软组织力学，从物理学的角度解决长期以来尚未解决的癌症起源问题。

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.