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Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53
- 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
- Subjects :
- 0301 basic medicine
Endosome
Sialoglycoproteins
Medizin
Medicine (miscellaneous)
exosomes
BAG6/CBP/p300-p53
Exosome
Monocytes
ESCRT
Metastasis
Extracellular Vesicles
Mice
03 medical and health sciences
0302 clinical medicine
melanoma
Tumor Microenvironment
medicine
metastasis
Animals
Humans
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Tumor microenvironment
Chemistry
Membrane Proteins
Nuclear Proteins
Acetylation
Phosphoproteins
medicine.disease
Peptide Fragments
Microvesicles
Cell biology
Mice, Inbred C57BL
Transplantation
Cell Transformation, Neoplastic
HEK293 Cells
030104 developmental biology
030220 oncology & carcinogenesis
Tumor Suppressor Protein p53
E1A-Associated p300 Protein
Reprogramming
Research Paper
Molecular Chaperones
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....09e7caa06220411bd26ff6c67ecb324f