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DOI: 10.1055/s-0039-3402104
YAP-induced tumor initiation mediates a switch in hepatic macrophage identity via the Ccl2/Ccr2 axis
Publikationsverlauf
Publikationsdatum:
03. Januar 2020 (online)
Background:
The development of hepatocellular carcinoma (HCC) precursor lesions includes the functional modulation of disease modifying non-parenchymal cells (NPCs). However, how oncogenes affect heterologous communication between tumor cells and NPCs is not well defined. Here, the impact of yes-associated protein (YAP)-induced chemokines in tumor initiation on liver macrophages is analysed.
Methods:
Transgenic mice with liver-specific expression of constitutively active YAP (LAP-tTA/YAPS127A) were used as HCC model. Immunofluorescence for Kupffer cell (KC) markers (Clec4f, F4/80) and a bone-marrow-derived macrophage (BMDM) marker (CD11b) were performed on mouse tissue specimens and correlated with vascular morphometric data. Murine blood plasma, primary hepatocytes and CD11b+ F4/80+ retinoid- macrophages from healthy and HCC precursor-bearing livers were used for proteomic and transcriptomic profiling. Immortalized THP-1 and SK-Hep1 cell lines served as in vitro model systems (e.g. chromatin-immunoprecipitation; ChIP). Human HCC expression data and tissue microarrays were analysed.
Results:
Bioinformatic analysis revealed that YAPS127A expressing hepatocytes showed a significant induction of a chemokine gene cluster. Increased CC-chemokine ligand 2 (Ccl2), CC-chemokine ligand 5 (Ccl5) and Macrophage colony-stimulating factor 1 (Csf1) levels were confirmed on protein levels in blood plasma. Ccl2 increased transmigration of macrophages and was transcriptionally regulated by the YAP/TEAD4 complex. Livers from YAPS127A mice were characterized by an increased macrophage recruitment, which lacked the KC phenotype. Importantly, these macrophages were defined by a lack of functional polarization (M0 signature), extravascular localization and high C-C motif chemokine receptor 2 (Ccr2) expression. Vascular morphometry revealed an increased branch length, junction formation and elevated vessel diameters in YAPS127A transgenic mice that correlated with the degree of macrophage infiltration. Lastly, the presence of an M0 signature was also detectable in human HCC and served as an identifier for poor clinical outcome.
Conclusion:
YAP-induced tumor initiation results in increased BMDM recruitment leading to a population-based phenotypic switch of the liver macrophage compartment. The Ccl2/Ccr2 axis directly governs the perivascular infiltration of macrophages to preneoplastic lesions where these cells contribute to vascular remodelling.