%0 Journal Article
%A Hübers, Corinne
%A Abdul Pari, Ashik Ahmed
%A Grieshober, Denise
%A Petkov, Martin
%A Schmidt, Alexander
%A Messmer, Tatjana
%A Heyer, Christian Moritz
%A Schölch, Sebastian
%A Kapel, Stephanie
%A Gengenbacher, Nicolas
%A Singhal, Mahak
%A Schieb, Benjamin
%A Fricke, Claudine
%A Will, Rainer
%A Remans, Kim
%A Utikal, Jochen
%A Reissfelder, Christoph
%A Schlesner, Matthias
%A Hodivala-Dilke, Kairbaan M
%A Kersten, Sander
%A Goerdt, Sergij
%A Augustin, Hellmut
%A Felcht, Moritz
%T Primary tumor-derived systemic nANGPTL4 inhibits metastasis.
%J Journal of experimental medicine
%V 220
%N 1
%@ 0022-1007
%C New York, NY
%I Rockefeller Univ. Press
%M DKFZ-2022-02496
%P e20202595
%D 2023
%Z #EA:A190#LA:A190# / DKFZ-ZMBH Alliance
%X Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36269299
%R 10.1084/jem.20202595
%U https://inrepo02.dkfz.de/record/182202