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Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53

Authors :
Bastian Dörsam
Hans Christian Reinhardt
Katrin Roth
Elke Pogge von Strandmann
Andrea Nist
Olga Shatnyeva
Hinrich P. Hansen
Katrin S Reiners
Andriy Kubarenko
Michael Hallek
Annette Paschen
Thorsten Stiewe
Maximiliane Schuldner
Gero Knittel
Sebastian Theurich
Florian Finkernagel
Rolf Müller
Source :
Theranostics
Publication Year :
2019

Abstract

Extracellular vesicles released by tumor cells contribute to the reprogramming of the tumor microenvironment and interfere with hallmarks of cancer including metastasis. Notably, melanoma cell-derived EVs are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. However, molecular insights into how vesicles are selectively packaged with cargo defining their specific functions remain elusive. Methods: Here, we investigated the role of the chaperone Bcl2-associated anthogene 6 (BAG6, synonym Bat3) for the formation of pro- and anti-tumor EVs. EVs collected from wildtype cells and BAG6-deficient cells were characterized by mass spectrometry and RNAseq. Their tumorigenic potential was analyzed using the B-16V transplantation mouse melanoma model. Results: We demonstrate that EVs from B-16V cells inhibit lung metastasis associated with the mobilization of Ly6Clow patrolling monocytes. The formation of these anti-tumor-EVs was dependent on acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. Genetic ablation of BAG6 and disruption of this pathway led to the release of a distinct EV subtype, which failed to suppress metastasis but recruited tumor-promoting neutrophils to the pre-metastatic niche. Conclusion: We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV cargo loading and thus a potential novel microenvironmental therapeutic target. CA extern

Details

Language :
English
Database :
OpenAIRE
Journal :
Theranostics
Accession number :
edsair.doi.dedup.....09e7caa06220411bd26ff6c67ecb324f