Role of tissue mechanical and metabolic properties in cancer formation studied in a translational liver tumor model

肝细胞癌（HCC）是全球癌症相关死亡的第三大常见原因。由于大多数HCC表现为肝硬化伴异质实质，早期和小的影像学表现异常的肿瘤可能会被忽略。在不可切除的HCC中，局部治疗是指南批准的，但经常因治疗不完全和复发而受到限制。虽然许多耐药机制正在研究中，但通过化学和机械信号传导，解除调控的细胞代谢在形成肿瘤微环境（TME）中起着关键作用。具体而言，HCC中血管和淋巴系统的功能失调破坏了物质运输和代谢通量，导致间质压力（固体应力）、细胞可塑性（组织流动性）和细胞外基质（ECM）的数量和组织（力学异质性）的变化。我们项目的主要假设是，机械和代谢组织特性的相互依赖变化可能通过促进致瘤生态位而先于形态肿瘤的形成，在这个生态位中，肿瘤增殖并对治疗产生耐药性。在本项目中，我们将使用翻译VX2兔肝肿瘤模型，利用新型PET-MRI研究肝肿瘤及其宿主肝脏体内力学和代谢的二元性。肿瘤与TME之间的机械相互作用可以通过多频MRE （mMRE）表征，而异常的糖代谢可以通过18F‐氟脱氧葡萄糖(FDG)-PET成像。由于FDG‐PET主要探测早期糖酵解，我们将采用创新的MRI技术，包括化学交换饱和转移（CEST）和磁共振光谱（MRS）来评估代谢。具体来说，CEST将成像糖原、谷氨酸或葡萄糖的代谢通量。MRS将评估组织酸度。肿瘤及其ECM的体内力学特性将使用具有适应硬件和序列的mMRE进行研究。使用纵向多参数定量(q)MRI和mMRE，我们旨在提供健康和肝硬化肝脏中肿瘤及其TME的机械和代谢特征。我们还将研究消融引起的肿瘤力学和代谢特性的变化，以确定导致不完全消融的转化模式。原位兔肿瘤模型能够在临床3T PET-MRI扫描仪上开发这种综合成像方案，并使用人体大小的设备进行消融，所有这些都有助于转化为临床常规。通过将我们的机械和代谢成像标记与代谢建模（A02）、干扰/解干扰分析（A03）、体内机械异质性（C01）、组织流动性（C02）和固体应力（C03）相结合，我们的目标是更深入地了解肝脏肿瘤及其TME在生物力学和代谢方面的动态相互作用，以确定早期肿瘤诊断、个性化治疗计划和治疗监测的生物标志物。

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. As most HCC manifests in cirrhotic livers with heterogenous parenchyma, early and small tumors with abnormal imaging appearance may be missed. In unresectable HCC, locoregional therapies are guideline-approved but are frequently limited by incomplete treatment and recurrence. While many resistance mechanisms are under investigation, the deregulated cellular metabolism plays a pivotal role in shaping the tumor microenvironment (TME) through chemical and mechanical signaling. Specifically, dysfunctional vascular and lymphatic systems in HCC disrupt mass transport and the metabolic flux, leading to changes of interstitial pressure (solid stress), cell plasticity (tissue fluidity), and the amount and organization of extracellular matrix (ECM) (mechanical heterogeneity). The main hypothesis of our project is that the interdependent changes of the mechanical and metabolic tissue properties may precede morphological tumor formation by promotion of a tumorigenic niche, in which tumors proliferate and become resistant to therapy. In this project, we will use the translational VX2 rabbit liver tumor model to investigate the duality of mechanics and metabolism in liver tumors and their host liver in vivo using novel PET-MRI. The mechanical interaction between tumor and TME can be characterized by multifrequency MRE (mMRE), while abnormal glucose metabolism can be imaged with 18F‐fluorodeoxyglucose (FDG)-PET. As FDG‐PET primarily probes early glycolysis, we will implement innovative MRI techniques including chemical exchange saturation transfer (CEST) and MR-spectroscopy (MRS) to assess metabolism. Specifically, CEST will image the metabolic flux of glycogen, glutamate, or glucose. MRS will assess tissue acidity. In vivo mechanical properties of the tumor and its ECM will be investigated using mMRE with an adapted hardware and sequence. Using longitudinal multiparametric quantitative (q)MRI and mMRE, we aim to provide a mechanical and metabolic profile of the tumor and its TME in healthy and cirrhotic livers. We will also investigate the changes of the mechanical and metabolic tumor properties induced by ablation to identify transformative patterns that lead to incomplete ablation. The orthotopic rabbit tumor model enables the development of this comprehensive imaging protocol on a clinical 3T PET-MRI scanner and ablation using human-size equipment, all of which facilitate translation into clinical routine. By combining our mechanical and metabolic imaging markers with metabolic modeling (A02), jamming/unjamming analysis (A03), and in vivo mechanical heterogeneity (C01), tissue fluidity (C02), and solid stress (C03), we aim to gain a deeper understanding of the dynamic interplay between the liver tumor and its TME regarding biomechanics and metabolism to identify biomarkers for early tumor diagnosis, personalized treatment planning, and therapeutic monitoring.