TY  - JOUR
AU  - Hübers, Corinne
AU  - Abdul Pari, Ashik Ahmed
AU  - Grieshober, Denise
AU  - Petkov, Martin
AU  - Schmidt, Alexander
AU  - Messmer, Tatjana
AU  - Heyer, Christian Moritz
AU  - Schölch, Sebastian
AU  - Kapel, Stephanie
AU  - Gengenbacher, Nicolas
AU  - Singhal, Mahak
AU  - Schieb, Benjamin
AU  - Fricke, Claudine
AU  - Will, Rainer
AU  - Remans, Kim
AU  - Utikal, Jochen
AU  - Reissfelder, Christoph
AU  - Schlesner, Matthias
AU  - Hodivala-Dilke, Kairbaan M
AU  - Kersten, Sander
AU  - Goerdt, Sergij
AU  - Augustin, Hellmut
AU  - Felcht, Moritz
TI  - Primary tumor-derived systemic nANGPTL4 inhibits metastasis.
JO  - Journal of experimental medicine
VL  - 220
IS  - 1
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DKFZ-2022-02496
SP  - e20202595
PY  - 2023
N1  - #EA:A190#LA:A190# / DKFZ-ZMBH Alliance
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36269299
DO  - DOI:10.1084/jem.20202595
UR  - https://inrepo02.dkfz.de/record/182202
ER  -