Pankreatische Sternzellen induzieren Tumorwachstum in verhärtetem Gewebe

In solid tumors the increased rigidity of the stroma is an essential barrier against the immune response and the efficient use of therapeutic drugs. The tumor cells of the pancreatic ductal adenocarcinoma (PDAC) can activate the stromal stellate cells (PSC) and thus the extracellular matrix (ECM) components like collagen and fibronectin are highly secreted. This excessive secretion leads to an increase in tissue rigidity which in turn influences the stromal PSCs and fibroblasts. Protein analysis showed a significant upregulation of the AMP-kinase (AMPK), a metabolic regulator of energy homeostasis, in cells on a hard surface. AMPK gets activated under starvation and regulates anabolic and catabolic processes for ATP regeneration. It is especially important in the hypoxic, nutrition-deficient environment of PDAC, even though its functions are not only pro- but also antitumorigenic. The antagonist of AMPK, mTOR, regulates the cell metabolism towards processes using ATP. However, a protein expression analysis showed no influence of soft and hard surfaces on the amount of protein. Therefore, the mechanism behind the regulation of protein expression due to different surface rigidities is AMPK-specific. Testing the half-life of AMPK on soft and hard surfaces showed a higher rate of proteasomal degradation in cells on a soft surface. This leads to the conclusion that in cells on a hard surface AMPK gets stabilized. Therefore, the cells have to sense the ECM composition and transduce this information to regulate the AMPK protein level inside the cell. The essential complexes for mechanosensing are the focal adhesions (FA), comprised of the transmembrane integrins and a variety of proteins for signal transduction. Integrins possess an α- and β-subunit and can get activated through binding of different ECM components. A screening process revealed the αV-subunit as a potential regulator of the AMPK on the protein expression. Downregulation of αV as well as the focal adhesion kinase (FAK) lead to a decrease in AMPK stability. The mechanism behind the increased stability of AMPK on a hard surface is consequently dependent on the focal adhesion proteins ItgαV and FAK. AMPK has a variety of functions inside the cell, one of which is the upregulation of macroautophagy to regain nutrition and therefore energy. Macroautophagy is the digestion of proteins, protein complexes and organelles in so-called autophagosomes under starvation. The increased AMPK protein expression on a hard surface led to a higher rate of autophagy in the cells. The data showed an increase in tumor cell proliferation on a hard surface due to a high level of autophagy in PSCs. In contrast, the knockout of the ItgαV gene in PSCs led to a destabilization of AMPK and hence the proliferative effect on tumor cells was lost. These findings show that the stabilization of AMPK in PSCs was essential for tumor cell proliferation and survival in PDAC. The results also give a new insight in the tumor-stroma interaction of PDAC and after further examination could be used as a potential strategy for cancer therapies.