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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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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
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author 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
author_facet 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
author_sort Hübers, Corinne
collection PubMed
description 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.
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spelling pubmed-95952062023-04-21 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 J Exp Med Article 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. Rockefeller University Press 2022-10-21 /pmc/articles/PMC9595206/ /pubmed/36269299 http://dx.doi.org/10.1084/jem.20202595 Text en © 2022 Hübers et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
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 tumor–derived systemic nANGPTL4 inhibits metastasis
title Primary tumor–derived systemic nANGPTL4 inhibits metastasis
title_full Primary tumor–derived systemic nANGPTL4 inhibits metastasis
title_fullStr Primary tumor–derived systemic nANGPTL4 inhibits metastasis
title_full_unstemmed Primary tumor–derived systemic nANGPTL4 inhibits metastasis
title_short Primary tumor–derived systemic nANGPTL4 inhibits metastasis
title_sort primary tumor–derived systemic nangptl4 inhibits metastasis
topic Article
url 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
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