YAP-induced tumor initiation mediates a switch in hepatic macrophage identity via the Ccl2/Ccr2 axis

S Thomann; S Weiler; T Wei; C Sticht; C De La Torre; M Tóth; N Gretz; C Ball; H Glimm; E Ryschich; P Schirmacher; K Breuhahn

doi:10.1055/s-0039-3402104

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2020; 58(01): e2
DOI: 10.1055/s-0039-3402104

Lectures Session I Basic Hepatology (Fibrogenesis, NPC, Transport): Friday, February 14, 2020, 1:25 pm – 2:10 pm, Lecture Hall P1

Georg Thieme Verlag KG Stuttgart · New York

YAP-induced tumor initiation mediates a switch in hepatic macrophage identity via the Ccl2/Ccr2 axis

Authors

S Thomann

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
S Weiler

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
T Wei

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
C Sticht

²Center of Medical Research, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
C De La Torre

²Center of Medical Research, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
M Tóth

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
N Gretz

²Center of Medical Research, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany
C Ball

³National Center of Tumor Diseases, Translational Medical Oncology, Dresden, Germany
H Glimm

³National Center of Tumor Diseases, Translational Medical Oncology, Dresden, Germany
E Ryschich

⁴University Hospital Heidelberg, Department of General Surgery, Heidelberg, Germany
P Schirmacher

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany
K Breuhahn

¹University Hospital Heidelberg, Institute of Pathology, Heidelberg, Germany

Abstract

Full Text

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/YAP^S127A) 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 YAP^S127A 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 YAP^S127A 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 YAP^S127A 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.