Exosome-mediated uptake of mast cell tryptase into the nucleus of melanoma cells: a novel axis for regulating tumor cell proliferation and gene expression

Fabio Rabelo Melo,Gunnar Pejler,Sebastin Santosh Martin,Christian P Sommerhoff

doi:10.1038/s41419-019-1879-4

Abstract

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.

Highlights

Mast cells (MCs) are hematopoietic cells of the immune system, classically well known for their detrimental impact on allergic reactions[1,2,3]
The absence of tryptase does not affect the ability of MCs to store chymase or carboxypeptidase A3 (CPA3), nor does the absence of tryptase affect the ability of MCs to undergo immunological activation[19,20,21]
These analyses revealed that co-culture of the melanoma cells with MCs caused a profound downregulation of the expression of GP100, indicating that MCs affect the phenotype of the melanoma cells (Fig. 1d)

Summary

Introduction

Mast cells (MCs) are hematopoietic cells of the immune system, classically well known for their detrimental impact on allergic reactions[1,2,3]. There are several studies in various animal models implicating MCs as detrimental players in malignant conditions[9,10,11]. MCs are characterized by a high content of lysosomelike secretory granules containing large amounts of various preformed bioactive compounds, including histamine, serotonin, various cytokines and growth factors, serglycin proteoglycans, and large amounts of MCrestricted proteases[12]. The latter include tryptases, chymases, and carboxypeptidase A3 (CPA3), of which tryptase and chymase are serine proteases whereas CPA3 is Zn-containing metalloprotease[13,14]. Previous studies have suggested that the MC-restricted proteases can contribute to the manifestations of numerous pathologies[12,15], but their possible contribution in malignant settings has Official journal of the Cell Death Differentiation Association

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Conclusion