Role of hepatic stellate cells in the selection and adaptation of metastasizing cancer cells inthe hepatic environment

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Within the first funding period, we have increased the body of evidence regarding the important role of hepatic stellate cells (HSCs) in liver metastasis. Particularly, we found that HGF (hepatocyte growth factor) is a central mediator of HSZ-mediated cancer cell activation. Moreover, we identified mTORC2 (mammalian Target of Rapamycin Complex 2) as a crucial signaling pathway in HSC/cancer cell interaction. In addition, preliminary data indicate that several key features of liver metastasis, such as motility and metabolism are critically affected by the HSC-cancer cell/mTORC2 axis. Therefore, our focus is the bidirectional interaction of HSCs with cancer cells upon modulation of mTORC2.Within the consortium we want to get a deeper insight into the regulatory mechanisms and the functional role of HSCs on the selection and adaptation of metastasizing cancer cells. Besides the direct HSC-cancer cell interaction, we will assess effects on the local microenvironment. Furthermore, experimental and therapeutic strategies for mTORC2 blockade will be assessed in different models. The modulation of the HSC-cancer cell interaction may prove to be effective in reducing liver metastasis and providing a survival benefit for patients by targeting both, cancer cells and the tumor microenvironment.