Primary tumor–derived systemic nANGPTL4 inhibits metastasis
Corinne Hübers, Ashik Ahmed Abdul Pari, Denise Grieshober, Martin Petkov, Alexander Schmidt, Tatjana Messmer, Christian Moritz Heyer, Sebastian Schölch, Stephanie S. Kapel, Nicolas Gengenbacher, Mahak Singhal, Benjamin Schieb, Claudine Fricke, Rainer Will, Kim Remans, Jochen Utikal, Christoph Reißfelder, Matthias Schlesner, Kairbaan Hodivala‐Dilke, Sander Kersten, Sergij Goerdt, Hellmut G. Augustin, Moritz Felcht
Abstract
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.