Universität zu Köln

Karg, Margarete M., John, Lukas ORCID: 0000-0001-8178-6890, Refaian, Nasrin ORCID: 0000-0001-8345-5972, Buettner, Christian, Rottmar, Tanja, Sommer, Jonas, Bock, Barbara, Resheq, Yazid J., Ksander, Bruce R., Heindl, Ludwig M., Mackensen, Andreas and Bosch, Jacobus J. (2022). Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma. Mol. Cancer Res., 20 (8). S. 1320 - 1337. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3125

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Abstract

Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma. Midkine expression in primary uveal melanoma significantly correlates with poor survival and is elevated in patients that develop metastatic disease. Monosomy 3 and histopathologic staging parameters are associated with midkine expression. In addition, we demonstrate that midkine promotes survival, migration across a barrier of hepatic sinusoid endothelial cells and resistance to AKT/mTOR inhibition. Fur-thermore, midkine is secreted and mediates mTOR activation by maintaining phosphorylation of the mTOR target RPS6 in uveal melanoma cells. Therefore, midkine is identified as a uveal melanoma cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as a new therapeutic target. Implications: Midkine is identified as a survival factor that drives liver metastasis and therapeutic resistance in melanoma of the eye.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Karg, Margarete M. UNSPECIFIED UNSPECIFIED UNSPECIFIED John, Lukas UNSPECIFIED orcid.org/0000-0001-8178-6890 UNSPECIFIED Refaian, Nasrin UNSPECIFIED orcid.org/0000-0001-8345-5972 UNSPECIFIED Buettner, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rottmar, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Sommer, Jonas UNSPECIFIED UNSPECIFIED UNSPECIFIED Bock, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Resheq, Yazid J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ksander, Bruce R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Heindl, Ludwig M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mackensen, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Bosch, Jacobus J. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-679489
DOI:	10.1158/1541-7786.MCR-20-0692
Journal or Publication Title:	Mol. Cancer Res.
Volume:	20
Number:	8
Page Range:	S. 1320 - 1337
Date:	2022
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3125
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR MIDKINE; SOMATIC MUTATIONS; CANCER CELLS; TUMOR-GROWTH; EXPRESSION; MIGRATION; CLASSIFICATION; SUPPRESSION; ACTIVATION; PROGNOSIS Multiple languages Oncology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67948