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PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression

The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cel...

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Autores principales: Sui, Lufei, Wang, Suming, Ganguly, Debolina, El Rayes, Tyler P., Askeland, Cecilie, Børretzen, Astrid, Sim, Danielle, Halvorsen, Ole Johan, Knutsvik, Gøril, Arnes, Jarle, Aziz, Sura, Haukaas, Svein, Foulkes, William D., Bielenberg, Diane R., Ziemys, Arturas, Mittal, Vivek, Brekken, Rolf A., Akslen, Lars A., Watnick, Randolph S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794699/
https://www.ncbi.nlm.nih.gov/pubmed/36575174
http://dx.doi.org/10.1038/s41467-022-35649-9
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author Sui, Lufei
Wang, Suming
Ganguly, Debolina
El Rayes, Tyler P.
Askeland, Cecilie
Børretzen, Astrid
Sim, Danielle
Halvorsen, Ole Johan
Knutsvik, Gøril
Arnes, Jarle
Aziz, Sura
Haukaas, Svein
Foulkes, William D.
Bielenberg, Diane R.
Ziemys, Arturas
Mittal, Vivek
Brekken, Rolf A.
Akslen, Lars A.
Watnick, Randolph S.
author_facet Sui, Lufei
Wang, Suming
Ganguly, Debolina
El Rayes, Tyler P.
Askeland, Cecilie
Børretzen, Astrid
Sim, Danielle
Halvorsen, Ole Johan
Knutsvik, Gøril
Arnes, Jarle
Aziz, Sura
Haukaas, Svein
Foulkes, William D.
Bielenberg, Diane R.
Ziemys, Arturas
Mittal, Vivek
Brekken, Rolf A.
Akslen, Lars A.
Watnick, Randolph S.
author_sort Sui, Lufei
collection PubMed
description The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic.
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spelling pubmed-97946992022-12-29 PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression Sui, Lufei Wang, Suming Ganguly, Debolina El Rayes, Tyler P. Askeland, Cecilie Børretzen, Astrid Sim, Danielle Halvorsen, Ole Johan Knutsvik, Gøril Arnes, Jarle Aziz, Sura Haukaas, Svein Foulkes, William D. Bielenberg, Diane R. Ziemys, Arturas Mittal, Vivek Brekken, Rolf A. Akslen, Lars A. Watnick, Randolph S. Nat Commun Article The progression of cancer from localized to metastatic disease is the primary cause of morbidity and mortality. The interplay between the tumor and its microenvironment is the key driver in this process of tumor progression. In order for tumors to progress and metastasize they must reprogram the cells that make up the microenvironment to promote tumor growth and suppress endogenous defense systems, such as the immune and inflammatory response. We have previously demonstrated that stimulation of Tsp-1 in the tumor microenvironment (TME) potently inhibits tumor growth and progression. Here, we identify a novel tumor-mediated mechanism that represses the expression of Tsp-1 in the TME via secretion of the serine protease PRSS2. We demonstrate that PRSS2 represses Tsp-1, not via its enzymatic activity, but by binding to low-density lipoprotein receptor-related protein 1 (LRP1). These findings describe a hitherto undescribed activity for PRSS2 through binding to LRP1 and represent a potential therapeutic strategy to treat cancer by blocking the PRSS2-mediated repression of Tsp-1. Based on the ability of PRSS2 to reprogram the tumor microenvironment, this discovery could lead to the development of therapeutic agents that are indication agnostic. Nature Publishing Group UK 2022-12-27 /pmc/articles/PMC9794699/ /pubmed/36575174 http://dx.doi.org/10.1038/s41467-022-35649-9 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sui, Lufei
Wang, Suming
Ganguly, Debolina
El Rayes, Tyler P.
Askeland, Cecilie
Børretzen, Astrid
Sim, Danielle
Halvorsen, Ole Johan
Knutsvik, Gøril
Arnes, Jarle
Aziz, Sura
Haukaas, Svein
Foulkes, William D.
Bielenberg, Diane R.
Ziemys, Arturas
Mittal, Vivek
Brekken, Rolf A.
Akslen, Lars A.
Watnick, Randolph S.
PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title_full PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title_fullStr PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title_full_unstemmed PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title_short PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression
title_sort prss2 remodels the tumor microenvironment via repression of tsp1 to stimulate tumor growth and progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9794699/
https://www.ncbi.nlm.nih.gov/pubmed/36575174
http://dx.doi.org/10.1038/s41467-022-35649-9
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