Interplay of mechanical properties of tissue microenvironment, oncogenic signaling, and metabolism in hepatopancreatic cancer

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Oncogenic signaling pathways are the main drivers of cellular transformation and metabolic alterations and lead to cancer cell invasion and metastasis. Intracellular molecular adaptation processes in cancer cells following oncogenic transformation have been widely studied. However, the link between mechanical alterations induced by the growing tumor and the interaction with the surrounding tissue microenvironment remains incompletely understood. In A02, we will combine a comprehensive molecular investigation of pancreatic adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) samples at RNA, protein, and metabolite levels with the determination of viscoelastic properties of patient tumors in vivo and in vitro. Thus, within the research unit, A02 is central to the analysis of tumor-altered metabolism and signaling concerning mechanical niche properties. With the support of A01 and A03, we will establish and apply organoid-matrix mechanical assays, while tissue and in vivo mechanical parameters will be obtained from the B- and C projects. To gain insight into molecular processes coupled with distinct and patient-individual viscoelastic properties, we will first uncover the transcriptomic and metabolic profiles of tumor samples derived from patients undergoing surgery and previously tested using multifrequency MR elastography (mMRE). In addition to intracellular processes activated through oncogenes, elevated external solid stress and interstitial fluid pressure have been shown to generate stress signals within tumors. This can impact MAPK, YAP/TAZ, and TGFβ pathway activation. To test the hypothesis that oncogenic signaling and metabolic properties are influenced by the mechanical environment within a tumor sample and vice-versa, organoids will be established from patient tissue with distinct viscoelastic properties investigated by mMRE. Distinct matrix components will be added to modulate in vitro matrix stiffness. Alternatively, organoids will be grown on pancreas and liver decellularized extracellular matrix samples. Using these different environmental conditions, we will implement transcriptomic and CyTOF analyses for determining KRAS/MAPK, mTOR, insulin, and glucagon signaling of PDAC and HCC to link metabolic states with oncogenic signaling. Using molecular resolved kinetic modeling based on proteomic data from parenchyma/tumors of pancreas and livers obtained from surgical specimens and organoids, we will reveal the alterations in metabolic capacities of carbohydrate, fatty acid, and amino acid metabolism. We will compare in vivo and ex vivo viscoelastic properties of patients and differentially cultivated organoids. Combining these data, we will identify clusters of signaling, metabolic states/dynamics under varying matrix conditions, and viscoelastic properties from patients to be the first to uncover functional links that have the potential to improve diagnosis and help to identify new therapeutic targets in patients with PDAC and HCC.