Universität zu Köln

Schuldner, Maximiliane, Doersam, Bastian, Shatnyeva, Olga, Reiners, Katrin S., Kubarenko, Andriy, Hansen, Hinrich P., Finkernagel, Florian, Roth, Katrin, Theurich, Sebastian ORCID: 0000-0001-5706-8258, Nist, Andrea, Stiewe, Thorsten ORCID: 0000-0003-0134-7826, Paschen, Annette, Knittel, Gero, Reinhardt, Hans C., Mueller, Rolf, Hallek, Michael and von Strandmann, Elke Pogge (2019). Exosome-dependent immune surveillance at the metastatic niche requires BAG6 and CBP/p300-dependent acetylation of p53. Theranostics, 9 (21). S. 6047 - 6063. LAKE HAVEN: IVYSPRING INT PUBL. ISSN 1838-7640

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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 Ly6C(low) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schuldner, Maximiliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Doersam, Bastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Shatnyeva, Olga UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiners, Katrin S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kubarenko, Andriy UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Hinrich P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Finkernagel, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Roth, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Theurich, Sebastian UNSPECIFIED orcid.org/0000-0001-5706-8258 UNSPECIFIED Nist, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Stiewe, Thorsten UNSPECIFIED orcid.org/0000-0003-0134-7826 UNSPECIFIED Paschen, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Knittel, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED von Strandmann, Elke Pogge UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-160751
DOI:	10.7150/thno.36378
Journal or Publication Title:	Theranostics
Volume:	9
Number:	21
Page Range:	S. 6047 - 6063
Date:	2019
Publisher:	IVYSPRING INT PUBL
Place of Publication:	LAKE HAVEN
ISSN:	1838-7640
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-ASSOCIATED TRANSCRIPT-3; MELANOMA PROGRESSION; EXTRACELLULAR VESICLES; NKP30 RECEPTOR; CELLS; EXPRESSION; RESPONSES; COMMUNICATION; BIOGENESIS; AUTOPHAGY Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/16075