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Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Ludwig Maximilians Univ Munchen, Univ Hosp, Inst Lab Med, Munich, Germany.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, Uppsala, Sweden.ORCID iD: 0000-0002-6779-391x
2019 (English)In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, article id 659Article in journal (Refereed) Published
Abstract [en]

It is well established that mast cell accumulation accompanies most malignancies. However, the knowledge of how mast cells functionally impact on tumors is still rudimentary. Here we addressed this issue and show that mast cells have anti-proliferative activity on melanoma cells and that this effect is dependent on tryptase, a tetrameric protease stored in mast cell granules. Mechanistically, tryptase was found to be endocytosed by melanoma cells as cargo of DNA-coated exosomes released from melanoma cells, followed by transport to the nucleus. In the nucleus, tryptase executed clipping of histone 3 and degradation of Lamin B1, accompanied by extensive nuclear remodeling. Moreover, tryptase degraded hnRNP A2/B1, a protein involved in mRNA stabilization and interaction with non-coding RNAs. This was followed by downregulated expression of the oncogene EGR1 and of multiple non-coding RNAs, including oncogenic species. Altogether, these findings establish a new principle for regulation of tumor cell proliferation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2019. Vol. 10, article id 659
National Category
Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-395846DOI: 10.1038/s41419-019-1879-4ISI: 000488849400002PubMedID: 31506436OAI: oai:DiVA.org:uu-395846DiVA, id: diva2:1365491
Funder
Swedish Research CouncilSwedish Cancer SocietySwedish Heart Lung FoundationKnut and Alice Wallenberg FoundationAvailable from: 2019-10-25 Created: 2019-10-25 Last updated: 2019-10-25Bibliographically approved

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