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.
Primary tumor–derived systemic nANGPTL4 inhibits metastasis
C. Hübers, A.A. Abdul Pari, and D. Grieshober contributed equally to this paper.
H.G. Augustin and M. Felcht contributed equally to this paper.
Disclosures: C. Hübers reported a patent to European Patent Agency no. 19 190 563.7 pending and a patent to European Patent Agency no. 21 156 649.2 pending. A.A. Abdul Pari reported a patent to EP 19 190 563.7 pending and a patent to EP 21 156 649.2 pending. D. Grieshober reported a patent to EP 21 156 649.2 pending. J.S. Utikal is on the advisory board or has received honoraria and travel support from Amgen, Bristol Myers Squibb, GSK, Immunocore, LeoPharma, Merck Sharp and Dohme, Novartis, Pierre Fabre, Roche, and Sanofi outside the submitted work. K.M. Hodivala-Dilke reported personal fees from Ellipses and non-financial support from Vasodynamics outside the submitted work. H.G. Augustin reported a patent to inhibition of metastasis development by nANGPTL-4 pending and a patent to nANGPTL4 as marker for disease progression pending. M. Felcht reported a patent to DKFZ/UHEI patent application “inhibition of metastasis development by nANGPLT4” pending and a patent to DKFZ/UHEI patent application “nANGPLT4 as marker for disease progression” pending. No other disclosures were reported.
