Primary tumor–derived systemic nANGPTL4 inhibits metastasis

• DOI: 10.1084/jem.20202595
• Publication Date: 2022-10-21T13:52:25Z
• Authors: Corinne Hübers; Ashik Ahmed Abdul...; Denise Grieshober; Martin Petkov; Alexander Schmidt; Tatjana Messmer; Christian Moritz ...; Sebastian Schölch; Stephanie S. Kapel; Nicolas Gengenbacher; Mahak Singhal; Benjamin Schieb; Claudine Fricke; Rainer Will; Kim Remans; Jochen Sven Utikal; Christoph Reissfe...; Matthias Schlesner; Kairbaan M. Hodiv...; Sander Kersten; Sergij Goerdt; Hellmut G. Augustin; Moritz Felcht
• Keywords: ddc:004; 0301 basic medicine; 0303 health sciences; 03 medical and health sciences; Neoplasms; Biomarkers, Tumor; Life Science; Humans; Angiopoietin-Like Protein 4; Angiopoietins; Article; Peptide Fragments

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.