A02

Mechanisms of vascular Wnt signaling during liver and lung homeostasis and tumorigenesis

Funding period: 2017-2029

Project A02

Project Leaders

Prof. Dr. Hellmut G. Augustin

 Project Leader A02

Abstract

The vascular control of organ function paradigm (‘angiocrine signaling’) is now well established, with the liver serving as a pioneering model. Endothelial cell-derived Wnt signals are essential for liver homeostasis and adaptive responses. We discovered that vascular Wnt ligands are mechanosensitive and act through dual autocrine and angiocrine mechanisms. Additionally, we identified hepatic stellate cell-derived Rspo3 as a key pericrine regulator of liver zonation, size, and function. Beyond homeostasis, vascular Wnt signals also shape disease progression, including tumor metastasis. Building on these findings, we will mechanistically dissect angiocrine and pericrine Wnt signaling mechanisms in the liver and the lungs during health and disease.

Project-related Publications

Hepatic stellate cells control liver zonation, size and functions via R-spondin 3

Sugimoto A, Saito Y, Wang G, Sun Q, Yin C, Lee KH, Geng Y, Rajbhandari P, Hernandez C, Steffani M, Qie J, Savage T, Goyal DM, Ray KC, Neelakantan TV, Yin D, Melms J, Lehrich BM, Yasaka TM, Liu S, Oertel M, Lan T, Guillot A, Peiseler M, Filliol A, Kanzaki H, Fujiwara N, Ravi S, Izar B, Brosch M, Hampe J, Remotti H, Argemi J, Sun Z, Kendall TJ, Hoshida Y, Tacke F, Fallowfield JA, Blockley-Powell SK, Haeusler RA, Steinman JB, Pajvani UB, Monga SP, Bataller R, Masoodi M, Arpaia N, Lee YA, Stockwell BR, Augustin HG, Schwabe RF. Nature. 2025 Mar 12.

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The spatial zonation of the murine placental vasculature is specified by epigenetic mechanisms

Gehrs S, Jakab M, Gutjahr E, Gu Z, Weichenhan D, Mallm JP, Mogler C, Schlesner M, Plass C, Schlereth K, Augustin HG. Dev Cell. 2025 Jan 9:S1534-5807(24)00776-7.

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Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency

Jakab M, Lee KH, Uvarovskii A, Ovchinnikova S, Kulkarni SR, Jakab S, Rostalski T, Spegg C, Anders S, Augustin HG. Nat Cancer. 2024 Feb 2. doi: 10.1038/s43018-023-00716-7. Online ahead of print. PMID: 38308117

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A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver

Inverso D, Shi J, Lee KH, Jakab M, Ben-Moshe S, Kulkarni SR, Schneider M, Wang G, Komeili M, Vélez PA, Riedel M, Spegg C, Ruppert T, Schaeffer-Reiss C, Helm D, Singh I, Boutros M, Chintharlapalli S, Heikenwalder M, Itzkovitz S, Augustin HG. Dev Cell. 2021 Jun 7;56(11):1677-1693.e10. PMID: 34038707

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Understanding angiodiversity: Insights from single cell biology

Jakab M, Augustin HG. Development. 2020 Aug 12;147(15):dev146621. doi: 10.1242/dev.146621. PMID: 32792338

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Tumor cell-derived Angiopoietin-2 promotes metastasis in melanoma

Abdul Pari AA, Singhal M, Hübers C, Mogler C, Schieb B, Gampp A, Gengenbacher N, Reynolds LE, Terhardt D, Géraud C, Utikal J, Thomas M, Goerdt S, Hodivala-Dilke KM, Augustin HG#, Felcht M.# Cancer Res. 2020 Jun 15;80(12):2586-2598. doi: 10.1158/0008-5472.CAN-19-2660. Epub 2020 Apr 17. (#equally contributing last authors) PMID: 32303578

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Preclinical validation of a novelmetastasis inhibiting Tie1 function-blocking antibody

Singhal M, Gengenbacher N, La Porta S, Gehrs S, Shi J, Kamiyama M, Bodenmiller DM, Fischl A, Schieb B, Besemfelder E, Chintharlapalli S, Augustin HG. EMBO Mol Med. 2020 Jun 8;12(6):e11164. doi: 10.15252/emmm.201911164. Epub 2020 Apr 17. PMID: 32302470

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Endothelial cell fitness dictates the source of regenerating liver vasculature

Singhal, M.#, X. Liu#, D. Inverso, K. Jiang, J. Dai, H. He, S. Bartels, W. Li, A.A. Abdul Pari, N. Gengenbacher, E. Besemfelder, L. Hui, H.G. Augustin§, J. Hu§. J Exp Med. 2018 Oct 1;215(10):2497-2508. doi: 10.1084/jem.20180008. Epub 2018 Sep 7. (#equally contributing first authors; §equally contributing senior authors). PMID: 30194265.

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The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium

Schlereth K, Weichenhan D, Bauer T, Heumann T, Giannakouri E, Lipka D, Jaeger S, Schlesner M, Aloy P, Eils R, Plass C, Augustin HG. Elife. 2018 May 11;7. PMID:29749927

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