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

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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.