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

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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.