TY - JOUR T1 - YAP orchestrates heterotypic endothelial cell communication via HGF/c-MET signaling in liver tumorigenesis JF - bioRxiv DO - 10.1101/2020.03.17.995225 SP - 2020.03.17.995225 AU - Stefan Thomann AU - Sofia M. E. Weiler AU - Simone Marquard AU - Claudia R. Ball AU - Marcell Tóth AU - Teng Wei AU - Carsten Sticht AU - Carolina De La Torre AU - Eduard Ryschich AU - Olga Ermakova AU - Carolin Mogler AU - Daniel Kazdal AU - Norbert Gretz AU - Hanno Glimm AU - Eugen Rempel AU - Peter Schirmacher AU - Kai Breuhahn Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/18/2020.03.17.995225.abstract N2 - Next to cell autonomous mechanisms, the oncogene yes-associated protein (YAP) controls liver tumor initiation and progression via cell extrinsic functions creating a tumor-supporting environment. However, how YAP affects the microenvironment and in particular the vascular niche, which contributes to liver disease and hepatocarcinogenesis, is poorly understood.In this study, histo-morphological and molecular characterization of murine liver endothelial cells (ECs) populations and human single cell data revealed the presence of liver sinusoidal endothelial cells (LSECs) and capillary endothelial cells (CECs) in healthy liver tissue. In YAPS127A-induced tumorigenesis, a gradual replacement of LSECs by CECs was associated with dynamic changes in the expression of genes involved in EC subtype-specific paracrine communication. The formation of new potential communication hubs connecting CECs and LSECs included the hepatocyte growth factor (Hgf)/c-Met signaling pathway. In hepatocytes and tumor cells, YAP/TEA domain transcription factor 4 (TEAD4)-dependent transcriptional induction of osteopontin (Opn) stimulated c-Met expression in ECs with CEC phenotype, which sensitized these cells to the pro-migratory effects of LSEC-derived Hgf. In human HCCs, the presence of a migration-associated tip-cell signature correlated with poor clinical outcome and the loss of LSEC marker gene expression. In addition, the replacement of LSECs by CECs with exclusive c-MET expression in a CEC subpopulation was confirmed at the single cell level.In summary, YAP-dependent changes of the liver vascular niche comprise the formation of heterologous communication hubs (e.g. the HGF/c-Met axis), in which tumor cell-derived factors modify the crosstalk between LSECs and CECs.CECcapillary endothelial cellECendothelial cellECMextracellular matrixHCChepatocellular carcinomaHgf/HGF*hepatocyte growth factorHSChepatic stellate cellLSECliver sinusoidal endothelial cellNPCnon-parenchymal cellOpnosteopontinYap/YAP*yes-associated protein ER -