Authors:	Ma, Junzhi Klemm, Janina Gerardo-Ramírez, Monserrat Frappart, Lucien Castven, Darko Becker, Diana Zoch, Ansgar Parent, Romain Bartosch, Birke Minnich, Kerstin Giovannini, Marco Danckwardt, Sven Hartmann, Nils Morrison, Helen Herrlich, Peter Marquardt, Jens U. Hartmann, Monika
Title:	Cluster of differentiation 44 promotes osteosarcoma progression in mice lacking the tumor suppressor Merlin
Online publication date:	5-Jul-2021
Year of first publication:	2020
Language:	english
Abstract:	Merlin is a versatile tumor suppressor protein encoded by the NF2 gene. Several lines of evidence suggest that Merlin exerts its tumor suppressor activity, at least in part, by forming an inhibitory complex with cluster of differentiation 44 (CD44). Consistently, numerous NF2 mutations in cancer patients are predicted to perturb the interaction of Merlin with CD44. We hypothesized that disruption of the Merlin-CD44 complex through loss of Merlin, unleashes putative tumor- or metastasis-promoting functions of CD44. To evaluate the relevance of the Merlin-CD44 interaction in vivo, we compared tumor growth and progression in Cd44-positive and Cd44-negative Nf2-mutant mice. Heterozygous Nf2-mutant mice were prone to developing highly metastatic osteosarcomas. Importantly, while the absence of the Cd44 gene had no effect on the frequency of primary osteosarcoma development, it strongly diminished osteosarcoma metastasis formation in the Nf2-mutant mice. In vitro assays identified transendothelial migration as the most prominent cellular phenotype dependent on CD44. Adhesion to endothelial cells was blocked by interfering with integrin α4β1 (very late antigen-4, VLA-4) on osteosarcoma cells and CD44 upregulated levels of integrin VLA-4 β1 subunit. Among other putative functions of CD44, which may contribute to the metastatic behavior, the passage through the endothelial cells also appears to be critical in vivo, as CD44 significantly promoted formation of lung metastasis upon intravenous injection of osteosarcoma cells into immunocompromised mice. Altogether, our results strongly suggest that CD44 plays a metastasis-promoting role in the absence of Merlin.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-6173
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY-NC
Information on rights of use:	https://creativecommons.org/licenses/by-nc/4.0/
Journal:	International journal of cancer 147 9
Pages or article number:	2564 2577
Publisher:	Wiley-Liss
Publisher place:	Bognor Regis
Issue date:	2020
ISSN:	1097-0215
Publisher URL:	https://doi.org/10.1002/ijc.33144
Publisher DOI:	10.1002/ijc.33144
Appears in collections:	JGU-Publikationen