VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.

Garcia Martin, Ana Bélen; Zwicky, Pascale; Gruber, Thomas; Matti, Christoph; Moalli, Federica; Stein, Jens Volker; Francisco, David; Enzmann, Gaby; Levesque, Mitchell P; Hewer, Ekkehard; Lyck, Ruth (2018). VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption. Journal of cerebral blood flow and metabolism, 271678X18775887. Sage 10.1177/0271678X18775887

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Melanoma is the most aggressive skin cancer in humans. One severe complication is the formation of brain metastasis, which requires extravasation of melanoma cells across the tight blood-brain barrier (BBB). Previously, VLA-4 has been assigned a role for the adhesive interaction of melanoma cells with non-BBB endothelial cells. However, the role of melanoma VLA-4 for breaching the BBB remained unknown. In this study, we used a mouse in vitro BBB model and imaged the shear resistant arrest of melanoma cells on the BBB. Similar to effector T cells, inflammatory conditions of the BBB increased the arrest of melanoma cells followed by a unique post-arrest behavior lacking immediate crawling. However, over time, melanoma cells intercalated into the BBB and compromised its barrier properties. Most importantly, antibody ablation of VLA-4 abrogated melanoma shear resistant arrest on and intercalation into the BBB and protected the BBB from barrier breakdown. A tissue microarray established from human brain metastasis revealed that indeed a majority of 92% of all human melanoma brain metastases stained VLA-4 positive. We propose VLA-4 as a target for the inhibition of brain metastasis formation in the context of personalized medicine identifying metastasizing VLA-4 positive melanoma.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Service Sector > Institute of Pathology
10 Strategic Research Centers > ARTORG Center for Biomedical Engineering Research > ARTORG Center - Gerontechnology and Rehabilitation
09 Interdisciplinary Units > Microscopy Imaging Center MIC

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Garcia Martin, Ana Bélen; Moalli, Federica; Stein, Jens Volker; Enzmann, Gaby; Hewer, Ekkehard and Lyck, Ruth

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0271-678X

Publisher:

Sage

Language:

English

Submitter:

Ekkehard Hewer

Date Deposited:

29 May 2018 09:37

Last Modified:

17 Jan 2019 15:13

Publisher DOI:

10.1177/0271678X18775887

PubMed ID:

29762071

Uncontrolled Keywords:

BBB leakage Blood–brain barrier in vitro live cell imaging melanoma brain metastasis tissue microarray very late antigen-4

URI:

https://boris.unibe.ch/id/eprint/116699

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