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

Author

Listed:
  • Lufei Sui

    (Boston Children’s Hospital
    Harvard Medical School)

  • Suming Wang

    (Boston Children’s Hospital
    Harvard Medical School
    Vigeo Therapeutics, 86A Sherman Street)

  • Debolina Ganguly

    (UT Southwestern)

  • Tyler P. El Rayes

    (Weill Cornell Medical College
    Weill Cornell Medical College
    Weill Cornell Medical College)

  • Cecilie Askeland

    (University of Bergen
    Haukeland University Hospital)

  • Astrid Børretzen

    (University of Bergen
    Haukeland University Hospital)

  • Danielle Sim

    (Boston Children’s Hospital)

  • Ole Johan Halvorsen

    (University of Bergen
    Haukeland University Hospital)

  • Gøril Knutsvik

    (University of Bergen
    Haukeland University Hospital)

  • Jarle Arnes

    (University of Bergen
    Haukeland University Hospital)

  • Sura Aziz

    (University of Bergen
    Haukeland University Hospital)

  • Svein Haukaas

    (Haukeland University Hospital)

  • William D. Foulkes

    (Jewish General Hospital
    McGill University)

  • Diane R. Bielenberg

    (Boston Children’s Hospital
    Harvard Medical School)

  • Arturas Ziemys

    (Houston Methodist Research Institute)

  • Vivek Mittal

    (Weill Cornell Medical College
    Weill Cornell Medical College
    Weill Cornell Medical College)

  • Rolf A. Brekken

    (UT Southwestern
    University of Bergen)

  • Lars A. Akslen

    (University of Bergen
    Haukeland University Hospital)

  • Randolph S. Watnick

    (Boston Children’s Hospital
    Harvard Medical School
    University of Bergen
    Haukeland University Hospital)

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.

Suggested Citation

  • 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 & W, 2022. "PRSS2 remodels the tumor microenvironment via repression of Tsp1 to stimulate tumor growth and progression," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35649-9
    DOI: 10.1038/s41467-022-35649-9
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    1. Rosandra N. Kaplan & Rebecca D. Riba & Stergios Zacharoulis & Anna H. Bramley & Loïc Vincent & Carla Costa & Daniel D. MacDonald & David K. Jin & Koji Shido & Scott A. Kerns & Zhenping Zhu & Daniel Hi, 2005. "VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche," Nature, Nature, vol. 438(7069), pages 820-827, December.
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