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

Lufei Sui, Suming Wang, Debolina Ganguly, Tyler P. El Rayes, Cecilie Askeland, Astrid Børretzen, Danielle Sim, Ole Johan Halvorsen, Gøril Knutsvik, Jarle Arnes, Sura Aziz, Svein Haukaas, William D. Foulkes, Diane R. Bielenberg, Arturas Ziemys, Vivek Mittal, Rolf A. Brekken, Lars A. Akslen and Randolph S. Watnick ()
Additional contact information
Lufei Sui: Boston Children’s Hospital
Suming Wang: Boston Children’s Hospital
Debolina Ganguly: UT Southwestern
Tyler P. El Rayes: Weill Cornell Medical College
Cecilie Askeland: University of Bergen
Astrid Børretzen: University of Bergen
Danielle Sim: Boston Children’s Hospital
Ole Johan Halvorsen: University of Bergen
Gøril Knutsvik: University of Bergen
Jarle Arnes: University of Bergen
Sura Aziz: University of Bergen
Svein Haukaas: Haukeland University Hospital
William D. Foulkes: Jewish General Hospital
Diane R. Bielenberg: Boston Children’s Hospital
Arturas Ziemys: Houston Methodist Research Institute
Vivek Mittal: Weill Cornell Medical College
Rolf A. Brekken: UT Southwestern
Lars A. Akslen: University of Bergen
Randolph S. Watnick: Boston Children’s Hospital

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-35649-9

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