Universität zu Köln

Mammadova-Bach, Elmina, Zigrino, Paola ORCID: 0000-0002-7470-0064, Brucker, Camille, Bourdon, Catherine, Freund, Monique, De Arcangelis, Adele ORCID: 0000-0003-1114-8441, Abrams, Scott I., Orend, Gertaud, Gachet, Christian and Mangin, Pierre Henri (2016). Platelet integrin alpha 6 beta 1 controls lung metastasis through direct binding to cancer cell-derived ADAM9. JCI Insight, 1 (14). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

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Abstract

Metastatic dissemination of cancer cells, which accounts for 90% of cancer mortality, is the ultimate hallmark of malignancy. Growing evidence suggests that blood platelets have a predominant role in tumor metastasis; however, the molecular mechanisms involved remain elusive. Here, we demonstrate that genetic deficiency of integrin alpha 6 beta 1 on platelets markedly decreases experimental and spontaneous lung metastasis. In vitro and in vivo assays reveal that human and mouse platelet alpha 6 beta 1 supports platelet adhesion to various types of cancer cells. Using a knockdown approach, we identified ADAM9 as the major counter receptor of alpha 6 beta 1 on both human and mouse tumor cells. Static and flow-based adhesion assays of platelets binding to DC-9, a recombinant protein covering the disintegrin-cysteine domain of ADAM9, demonstrated that this receptor directly binds to platelet alpha 6 beta 1. In vivo studies showed that the interplay between platelet alpha 6 beta 1 and tumor cell-expressed ADAM9 promotes efficient lung metastasis. The integrin alpha 6 beta 1-dependent platelet-tumor cell interaction induces platelet activation and favors the extravasation process of tumor cells. Finally, we demonstrate that a pharmacological approach targeting alpha 6 beta 1 efficiently impairs tumor metastasis through a platelet-dependent mechanism. Our study reveals a mechanism by which platelets promote tumor metastasis and suggests that integrin alpha 6 beta 1 represents a promising target for antimetastatic therapies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mammadova-Bach, Elmina UNSPECIFIED UNSPECIFIED UNSPECIFIED Zigrino, Paola UNSPECIFIED orcid.org/0000-0002-7470-0064 UNSPECIFIED Brucker, Camille UNSPECIFIED UNSPECIFIED UNSPECIFIED Bourdon, Catherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Freund, Monique UNSPECIFIED UNSPECIFIED UNSPECIFIED De Arcangelis, Adele UNSPECIFIED orcid.org/0000-0003-1114-8441 UNSPECIFIED Abrams, Scott I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Orend, Gertaud UNSPECIFIED UNSPECIFIED UNSPECIFIED Gachet, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Mangin, Pierre Henri UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-262435
DOI:	10.1172/jci.insight.88245
Journal or Publication Title:	JCI Insight
Volume:	1
Number:	14
Date:	2016
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	2379-3708
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RANDOMIZED-CONTROLLED-TRIALS; JUNCTIONAL EPIDERMOLYSIS-BULLOSA; INCREASED EXPRESSION; TUMOR PROGRESSION; PANCREATIC-CANCER; PROSTATE-CANCER; BONE METASTASIS; MELANOMA-CELLS; MESSENGER-RNA; IN-VITRO Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26243