Exosome-dependent immune surveillance at the metastatic niche requires BAG6

ABSTRACT: Extracellular vesicles (EVs) secreted by tumor cells are able to establish a pre-metastatic niche in distant organs, or on the contrary, exert anti-tumor activity. The mechanisms directing distinct EV functions are unknown. Using the B-16V transplantation mouse melanoma model we demonstrate that EVs from B-16V cells mobilize Ly6Clow patrolling monocytes and inhibit lung metastasis. Mechanistically, the formation of anti-tumor-EVs was dependent on the chaperone BAG6 and the acetylation of p53 by the BAG6/CBP/p300-acetylase complex, followed by the recruitment of components of the endosomal sorting complexes required for transport (ESCRT) via a P(S/T)AP double motif of BAG6. By contrast, deficiency of BAG6 led to the release of a distinct vesicle subtype with pro-tumorigenic activity, which recruited neutrophils to the pre-metastatic niche. In humans, BAG6 expression decreases in late-stage melanoma patients, correlating with an increase of the mRNA for the metastasis driver alpha-catulin in EVs, as observed in BAG6-deficient mouse EVs. We conclude that the BAG6/CBP/p300-p53 axis is a key pathway directing EV-formation and function.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Urine

SUBMITTER: Christian Frese  

LAB HEAD: Christian Frese

PROVIDER: PXD010677 | Pride | 2019-11-12

REPOSITORIES: Pride