Primary tumor-derived systemic nANGPTL4 inhibits metastasis

Hübers, Corinne; Abdul Pari, Ashik Ahmed; Grieshober, Denise; Petkov, Martin; Schmidt, Alexander; Messmer, Tatjana; Heyer, Christian Moritz; Schölch, Sebastian; Kapel, Stephanie S.; Gengenbacher, Nicolas; Singhal, Mahak; Schieb, Benjamin; Fricke, Claudine; Will, Rainer; Remans, Kim; Utikal, Jochen Sven; Reissfelder, Christoph; Schlesner, Matthias; Hodivala-Dilke, Kairbaan M.; Kersten, Sander; Goerdt, Sergij; Augustin, Hellmut G.; Felcht, Moritz


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.