Cooperative and exclusive functions of Hippo pathway effectors in liver cancer

• Applicant: Professor Dr. Kai Breuhahn
• Subject Area: Pathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 505755359

The Hippo signaling pathway and its two effector molecules YAP and TAZ play a key role in mammalian organogenesis as well as tissue regeneration and - in case of dysregulation - carcinogenesis. We and others showed that the transcriptional co-activators YAP and TAZ control tumor cell proliferation, stemness, and chromosomal instability in liver cancer (HCC). Due to the relevance of YAP/TAZ in hepatocarcinogenesis (and other solid tumor types), it is not surprising that several pharmaceutical companies, such as Merck Healthcare KGaA, Roche, Novartis, Vivace Therapeutics, Genentech, and Inventiva developed YAP/TAZ inhibitors, which are currently tested in clinical trials. However, our recent data illustrate that next to tumor cell intrinsic effects, YAP/TAZ control the formation of heterologous cell communication networks connecting hepatocytes/HCC cells with non-tumorous liver-resident cells (liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs)). Long-time perturbation of YAP/TAZ in mouse livers cause unwanted side effects and aberrant communication patterns with likely implications on the applicability of YAP/TAZ inhibitors in cancer patients. In addition, preliminary data illustrate that YAP and TAZ are differentially expressed in LSEC, KC, and HSC populations (called non-parenchymal cells; NPCs). Thus, NPCs would also be affected by systemic treatment with pharmacological YAP/TAZ inhibitors. Based on this, we draw the following conclusions: - Combined YAP/TAZ inhibition in (liver) tumor cells is one strategy for cancer patients with Hippo pathway dysregulation; however, unpredictable extrinsic effects on heterologous cell communication in the liver must be expected. - YAP and TAZ are potent oncogenes; however, their function partly differs in tumor cells as well as their expression and function in NPC populations. In this grant application 3 work packages are suggested that comparatively unravel the complex role of YAP and TAZ in tumor cells and especially NPCs: WP1) Identification of communication networks initiated by oncogenic YAP/TAZ in HCC cells. WP2-A) Identification of common and mutually exclusive YAP/TAZ binding partners in NPCs. WP2-B) Characterization of YAP/TAZ downstream effector mechanisms and YAP/TAZ-dependent communication networks in NPCs. WP3) Confirmation of findings in suitable in vivo model systems. In summary, this project will decipher YAP- and/or TAZ-dependent molecular mechanisms in liver tumor cells and non-malignant liver-resident cells, which form communication hubs. Decoding these hubs will not only allow to understand side effects that become manifested during YAP/TAZ-directed therapy in patients. These data will also lay the basis to create therapeutic strategies through targeting mutual exclusive downstream effector mechanisms of YAP and TAZ in malignant and non-malignant cells.

• DFG Programme: Research Grants