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Primary tumor–derived systemic nANGPTL4 inhibits metastasis

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 antitumo...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9595206/
https://www.ncbi.nlm.nih.gov/pubmed/36269299
http://dx.doi.org/10.1084/jem.20202595
Descripción
Sumario: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.