C01 Multiscale mechanical properties of tumors and tumor environment – from tissue specimens to patients

超过80%的肝细胞癌(肝细胞癌)发现于肝纤维化或肝硬变，提示肝纤维化为肿瘤的发展创造了癌前环境。然而，对于肝癌在不同实质环境中的不同侵袭性的原因却知之甚少。在肝癌的发生过程中，多种机制和不同的细胞遗传学途径共同上调生长因子信号，并与机械性能的变化密切相关，这可以通过磁共振成像检测到。和肝细胞癌一样，胰腺导管腺癌(PDAC)通常被诊断为晚期，肝脏是转移的主要部位。在肿瘤进展过程中，PDAC和肝癌细胞经历上皮-间充质转化，这种转化可以通过改变肿瘤间质的机械特性来触发和促进。本研究的目的是利用体内多参数定量磁共振成像(QMRI)、断层弹性成像和多尺度多频率磁共振成像(MMRE)从物理学的角度研究肿瘤和生态位的共同进化。为此，我们计划开发用于自动纹理分析的工具，以基于硬度和流动性图揭示体内组织的力学异质性。结合体外多参数qMRI/mMRE、临床血清标记物和组织病理学，我们的目标是识别肝脏和胰腺恶性肿瘤壁龛的机械特征。我们假设体内肝胰腺肿瘤的发展受到肿瘤与微环境之间的机械相互作用的严重影响。生物物理和生物力学成像参数，包括粘弹性弥散、力学异质性和固体应力，可以帮助识别预测肿瘤侵袭性、恶变和治疗反应的生物力学特征。这个子项目的目标是开发新的成像标记物，可以检测肿瘤/壁龛组织机械特性的空间异质性，并评估硬度离散度、异质性和组织流动性如何随着肝细胞癌、肝转移和PDAC的进展而变化。我们将创建一个跨越组织长度尺度的肝脏和胰腺肿瘤患者和手术切除组织样本的生物物理和生物力学特征的库。为了创建预测肿瘤成像标志物的路线图，我们将与C03和协调项目合作，编制一个肿瘤生物物理属性和临床参数的数据库。C01是我们研究单位的关键组成部分，收集肝胰腺肿瘤的临床影像数据，用于分析机械异质性、弥散性(C02)和固体应力(C03)，并为各种分析提供组织，包括肿瘤-基质相互作用的微观力学研究(A01)、干扰/非干扰分析(A03)、代谢分析(A02)以及肝和胰腺肿瘤的脱细胞/再细胞化(B03)。

More than 80% of hepatocellular carcinomas (HCC) are found in fibrotic or cirrhotic livers, suggesting that liver fibrosis creates a premalignant environment for tumor development. However, little is known about the causes of the differential aggressiveness of HCC in different parenchymal environments. During hepatocarcinogenesis, multiple mechanisms and distinct cytogenetic pathways collectively upregulate growth factor signaling and are closely associated with changes in mechanical properties, which can be detected by MRE. Like HCC, pancreatic ductal adeno-carcinoma (PDAC) is often diagnosed at advanced stages with the liver as the main site of metastases. During tumor progression, PDAC and HCC cells undergo epithelial-mesenchymal transition, which can be triggered and promoted by altering the mechanical properties of the tumor stroma. The objective here is to use in vivo multiparametric quantitative MRI (qMRI), tomoelastography and multiscale-multifrequency MRE (mMRE) for investigating the coevolution of tumor and niche from a physics perspective. To this end, we plan to develop tools for automated texture analysis to reveal the mechanical heterogeneity of in vivo tissue based on stiffness and fluidity maps. Together with ex vivo multiparametric qMRI/mMRE, clinical serum markers, and histopathology, we aim to identify the mechanical signature of malignant tumor niches in the liver and pancreas. We hypothesize that the development of hepato-pancreatic tumors in vivo is critically influenced by the mechanical interactions between tumor and microenvironment. Biophysical and biomechanical imaging parameters including viscoelastic dispersion, mechanical heterogeneity, and solid stress can help identify the biomechanical traits that predict tumor aggressiveness, malignant transformation, and response to therapy. The goal of this sub-project is to develop novel imaging markers that can detect spatial heterogeneity in the mechanical properties of tumor/niche tissues and evaluate how stiffness dispersion, heterogeneity, and tissue fluidity change with the progression of HCC, liver metastases, and PDAC. We will create a library of the biophysical and biomechanical hallmarks of hepatic and pancreatic tumors in patients and surgically resected tissue samples across tissue length scales. To create a roadmap of predictive tumor imaging markers, we will compile a database of tumor biophysical properties and clinical parameters in collaboration with C03 and the coordination project. C01 is a key component of our research unit, acquiring clinical imaging data of hepato-pancreatic tumors for analysis of mechanical heterogeneity, dispersion (C02), and solid stress (C03), and providing tissues for various analyses including micromechanical studies of tumor-matrix interactions (A01), jamming/unjamming analyses (A03), metabolic profiling (A02), and decellularization/recellularization of hepatic and pancreatic tumors (B03).