B03 Scaffold composition and fluid pressure in recellularized hepatic and pancreatic tumors

B03 再细胞化肝和胰腺肿瘤中的支架组成和流体压力

• 批准号: 530848218
• 负责人: Dr. Jing Guo, Ph.D.
• 金额: --
• 依托单位: Chirurgische Klinik (CVK)
• 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/530848218?language=en
• 关键词: B03; Scaffold; composition; fluid; pressure

The importance of the mechanical traits of the extracellular matrix (ECM) and their influence on the progression of hepatic and pancreatic tumors is increasingly recognized. For example, end-stage chronic liver diseases are characterized by marked ECM structural changes that lead to abnormally high stiffness. Hepatocellular carcinoma (HCC) predominantly develops in stiff livers, suggesting that collagen deposition promotes tumorigenesis. Similar changes in the ECM influence tumor proliferation and chemoresistance in pancreatic ductal adenocarcinoma (PDAC) which is often associated with pronounced desmoplastic reaction. Under the influence of the altered ECM structure, mechanosensitive oncogenic signaling pathways are activated, dynamically enhancing the mechanical reciprocity between cells and ECM. The changes in mechano-signaling will initiate malignant transformation, collective multicellular migration, and angiogenesis of immature leaky vessels that increase intra-tumoral fluid pressure. Our main hypothesis underlying this project is that tumor development, growth and progression can be regulated by the tumor-hosting ECM through variation of its viscoelastic properties. However, the underlying mechanisms of reciprocal mechano-sensing between cells and ECM - especially during the critical phase of early tumor development - are not fully understood. Moreover, there is a lack of research exploring these mechanisms 3D bulk tissue with systematic and longitudinal monitoring by multiparametric quantitative MRI (qMRI) and multifrequency MR elastography (mMRE). Therefore, in B03 we will modulate scaffold composition and fluid pressure in decellularized and recellularized hepatic and pancreatic tumors. To test our hypothesis, we will first couple a bioreactor to a tabletop MRI scanner for ex vivo qMRI/mMRE imaging while maintaining the tissue’s viability during longitudinal investigations. Using this newly developed imaging device, we will investigate the biophysical properties of the decellularized and recellularized tumor-bearing liver and pancreatic tissue from patients. Together with other projects in the research unit, we will obtain gene expression profiles (B01), ECM proteomics (A02), quantification of solid stress (C03), and histological data for jamming/unjamming analysis (A03) to determine the role of biomechanics during cancer progression. Within this research unit, B03 will be responsible for the development of a bioreactor that fits into tabletop MRE for characterizing the biophysical properties of ex vivo tissues. In addition, using a well-defined, tissue-derived, three-dimensional matrix for tumor models, B03 will provide fundamental knowledge and in-depth understanding of the interplay between tumor and its surrounding. This will inform the identification of imaging biomarkers for the detection and prediction of mechanical tumor niche properties that favor tumor progression and treatment resistance, as addressed in this research unit.

细胞外基质（ECM）的力学特性及其对肝脏和胰腺肿瘤进展的影响的重要性越来越被认识到。例如，终末期慢性肝病的特征在于导致异常高硬度的显著ECM结构变化。肝细胞癌（HCC）主要发生在僵硬的肝脏，这表明胶原沉积促进肿瘤发生。ECM的类似变化影响胰腺导管腺癌（PDAC）的肿瘤增殖和化疗耐药性，这通常与明显的促纤维增生反应有关。在改变的ECM结构的影响下，机械敏感性致癌信号传导途径被激活，动态增强细胞和ECM之间的机械相互作用。机械信号的变化将引发恶性转化、集体多细胞迁移和未成熟渗漏血管的血管生成，从而增加肿瘤内流体压力。我们的主要假设是，肿瘤的发展，生长和进展可以调节肿瘤宿主ECM通过其粘弹性的变化。然而，细胞和ECM之间相互机械感应的潜在机制-特别是在早期肿瘤发展的关键阶段-尚未完全理解。此外，还缺乏通过多参数定量MRI（qMRI）和多频MR弹性成像（mMRE）进行系统和纵向监测来探索这些机制的3D大块组织的研究。因此，在B 03中，我们将调节脱细胞化和再细胞化的肝和胰腺肿瘤中的支架组成和流体压力。为了检验我们的假设，我们将首先将生物反应器耦合到台式MRI扫描仪，用于离体qMRI/mMRE成像，同时在纵向研究期间保持组织的活力。使用这种新开发的成像设备，我们将研究患者的脱细胞和再细胞化的荷瘤肝脏和胰腺组织的生物物理特性。与研究单位的其他项目一起，我们将获得基因表达谱（B 01），ECM蛋白质组学（A02），固体应力的定量（C 03）和用于干扰/解干扰分析的组织学数据（A03），以确定生物力学在癌症进展中的作用。在该研究单位内，B 03将负责开发适合桌面MRE的生物反应器，用于表征离体组织的生物物理特性。此外，B 03使用定义明确的、组织衍生的三维肿瘤模型矩阵，将提供对肿瘤及其周围环境之间相互作用的基础知识和深入理解。这将为识别成像生物标志物提供信息，用于检测和预测有利于肿瘤进展和治疗抗性的机械肿瘤生态位特性，如本研究单元所述。