Project Details
Projekt
Connecting intercellular cell junctions with Hippo/YAP pathway activity in hepatocytes and liver tumor cells
Applicant
Professor Dr. Kai Breuhahn
Subject Area
Cell Biology
Term
from 2019 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 414059188
Distinct dynamic expression changes of junctional proteins (classical and desmosomal cadherins) are detectable in liver under physiological and patho-physiological processes suggesting the existence of mechanisms responsible for the reorganization of cell-cell contact. Because first data for the cadherins CDH1/E-cadherin and FAT1 indicate a direct regulatory role via partly different mechanisms on the organ size-controlling and cell density-sensing cellular Hippo/yes-associated protein (YAP) signalling pathway, we hypothesise that the rearrangement of junctional structures such as adherens junctions (AJs) and desmosomes may facilitate their biological properties through this pathway. Indeed, first preliminary data reveal the up- or downregulation of some but not all cadherins in e.g. liver cancer development, which correlates with the induction of YAP-dependent signatures in hepatocellular cells. However, so far it is not understood, which type of junctional reorganisation can affect the Hippo/YAP pathway and if these changes are of functional relevance for liver hepatocytes or for malignantly transformed cells.The aim of this project is to describe how a panel of cadherins can modulate hepatocellular biology via the Hippo/YAP signalling axis under physiological and patho-physiological conditions. For this we will focus on the following aspects: 1) Identification of junctional structures that modulate the Hippo pathway and its downstream effector YAP2) Analysis of the molecular mechanisms connecting junctional structures with the Hippo kinase cassette or YAP3) Confirmation of biological relevance in a liver carcinogenesis.Using techniques from molecular biology, biochemistry, and cell biology as well as suitable mouse models, we will decipher if and how specific modifications of junctional structures can 'adjust' the spatial orientation of hepatocytes under physiological conditions and if these changes may, if permanently changed, can participate in the development of diseases such as cancer via the Hippo/YAP axis. These techniques include inducible systems for the expression of shRNAs/cDNAs, interactome studies using the Bio-ID approach, 3D sandwich cultures, as well as hydrodynamic gene delivery for the fast, efficient and stable genetic manipulation of hepatocytes in vivo. Lastly, we aim to substantiate the relevance of our findings in human cohorts of liver cancer patients, where abolishment of cell-cell contacts and activation of YAP is a frequent event in carcinogenesis.
DFG Programme
Priority Programmes
