Journal Article

DKFZ-2024-00485

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication.

Liu, K. ; Wehling, L. ; Wan, S. ; Weiler, S. M. E. ; Tóth, M. ; Ibberson, D. ; Marhenke, S. ; Ali, A.DKFZ* ; Lam, M.DKFZ* ; Guo, T. ; Pinna, F. ; Pedrini, F. ; Damle-Vartak, A. ; Dropmann, A. ; Rose, F. ; Colucci, S. ; Cheng, W. ; Bissinger, M. ; Schmitt, J. ; Birner, P. ; Poth, T. ; Angel, P.DKFZ* ; Dooley, S. ; Muckenthaler, M. U. ; Longerich, T. ; Vogel, A. ; Heikenwälder, M.DKFZ* ; Schirmacher, P. ; Breuhahn, K.

2024
Springer International Publishing AG Cham (ZG)

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Please use a persistent id in citations: doi:10.1007/s00018-024-05126-1

Abstract: The Hippo pathway and its transcriptional effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are targets for cancer therapy. It is important to determine if the activation of one factor compensates for the inhibition of the other. Moreover, it is unknown if YAP/TAZ-directed perturbation affects cell-cell communication of non-malignant liver cells.To investigate liver-specific phenotypes caused by YAP and TAZ inactivation, we generated mice with hepatocyte (HC) and biliary epithelial cell (BEC)-specific deletions for both factors (YAPKO, TAZKO and double knock-out (DKO)). Immunohistochemistry, single-cell sequencing, and proteomics were used to analyze liver tissues and serum.The loss of BECs, liver fibrosis, and necrosis characterized livers from YAPKO and DKO mice. This phenotype was weakened in DKO tissues compared to specimens from YAPKO animals. After depletion of YAP in HCs and BECs, YAP expression was induced in non-parenchymal cells (NPCs) in a cholestasis-independent manner. YAP positivity was detected in subgroups of Kupffer cells (KCs) and endothelial cells (ECs). The secretion of pro-inflammatory chemokines and cytokines such as C-X-C motif chemokine ligand 11 (CXCL11), fms-related receptor tyrosine kinase 3 ligand (FLT3L), and soluble intercellular adhesion molecule-1 (ICAM1) was increased in the serum of YAPKO animals. YAP activation in NPCs could contribute to inflammation via TEA domain transcription factor (TEAD)-dependent transcriptional regulation of secreted factors.YAP inactivation in HCs and BECs causes liver damage, and concomitant TAZ deletion does not enhance but reduces this phenotype. Additionally, we present a new mechanism by which YAP contributes to cell-cell communication originating from NPCs.

Keyword(s): Animals (MeSH) ; Mice (MeSH) ; Endothelial Cells (MeSH) ; Ligands (MeSH) ; Liver (MeSH) ; Hepatocytes (MeSH) ; Cell Communication (MeSH) ; Cholangiocyte ; Endothelial cell ; Hepatocyte ; Hippo pathway ; Kupffer cell ; Liver damage ; Proteomics ; Single-cell analysis ; TAZ ; Ligands

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Contributing Institute(s):

1. Chronische Entzündung und Krebs (F180)
2. Chronische Entzündung und Krebs (D440)
3. A100 Signaltransduktion/ Wachstumskontrolle (A100)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; BIOSIS Reviews Reports And Meetings ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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