YAP-induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer
Background & aim The development of hepatocellular carcinoma (HCC) is associated with the formation of communication networks leading to the recruitment of disease-modifying macrophages. However, how oncogenes in tumour cells control paracrine communication is not fully understood. Methods Trans...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2021
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| In: |
Liver international
Year: 2021, Volume: 41, Issue: 12, Pages: 3011-3023 |
| ISSN: | 1478-3231 |
| DOI: | 10.1111/liv.15048 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1111/liv.15048 Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.15048 
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| Author Notes: | Stefan Thomann, Sofia M. E. Weiler, Teng Wei, Carsten Sticht, Carolina De La Torre, Marcell Tóth, Fabian Rose, Yingyue Tang, Thomas Ritz, Claudia Ball, Hanno Glimm, Eduard Ryschich, Peter Schirmacher, Kai Breuhahn |
| Summary: | Background & aim The development of hepatocellular carcinoma (HCC) is associated with the formation of communication networks leading to the recruitment of disease-modifying macrophages. However, how oncogenes in tumour cells control paracrine communication is not fully understood. Methods Transgenic mice with liver-specific expression of the constitutively active yes-associated protein (YAPS127A) or an orthotopic implantation model served as tumour models. FACS-sorted F4/80+/CD11bdim/CD146-/retinoid- macrophages from healthy and tumour-bearing livers were used for transcriptomic profiling. Expression data of 242 human HCCs and a tissue microarray consisting of 91 HCCs and seven liver tissues were analyzed. Results Screening of primary tumour cells expressing YAPS127A identified CC chemokine ligand 2 (Ccl2) as a macrophage chemoattractant, whose expression was regulated in a YAP/TEA domain family member 4 (TEAD4)-dependent manner. Ccl2 expression was associated with a loss of Kupffer cells (KCs) and an increase in immature macrophages (Mɸimm) in hepatocarcinogenesis. Recruited Mɸimm were characterized by a lack of functional polarization (M0 signature) and high expression of the Ccl2 receptors C-C motif chemokine receptor 2 (Ccr2), C-X3-C motif chemokine receptor 1 (Cx3cr1) and pro-angiogenic platelet-derived growth factors (Pdgfa/Pdgfb). Mɸimm formed cellular clusters in the perivascular space, which correlated with vascular morphometric changes indicative for angiogenesis. In human HCCs, the M0 signature served as an identifier for poor clinical outcome and CCL2 correlated with YAP expression and vascular network formation. Conclusions In conclusion, YAP/TEAD4-regulated Ccl2 associates with perivascular recruitment of unpolarized Mɸimm and may contribute to a proangiogenic microenvironment in liver cancer. |
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| Item Description: | Gesehen am 08.08.2023 |
| Physical Description: | Online Resource |
| ISSN: | 1478-3231 |
| DOI: | 10.1111/liv.15048 |