Glycoprotein non-metastatic melanoma protein B promotes tumor growth and is a biomarker for lymphangioleiomyomatosis

in Endocrine-Related Cancer
Authors:
Erin Gibbons Department of Microbiology and Immunology University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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Manisha Taya Division of Hematology and Oncology, UT Southwestern, Dallas, Texas, USA

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Huixing Wu Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Samia H Lopa Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA

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Joel Moss Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI), NIH, Bethesda, Maryland, USA

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Elizabeth P Henske Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

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Francis X McCormack Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, Ohio, USA

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Stephen R Hammes Department of Microbiology and Immunology University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

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https://orcid.org/0000-0002-7367-276X

Correspondence should be addressed to S R Hammes: stephen_hammes@urmc.rochester.edu
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Lymphangioleiomyomatosis (LAM) is a rare, progressive cystic lung disease affecting almost exclusively female-sexed individuals. The cysts represent regions of lung destruction caused by smooth muscle tumors containing mutations in one of the two tuberous sclerosis (TSC) genes. mTORC1 inhibition slows but does not stop LAM advancement. Furthermore, monitoring disease progression is hindered by insufficient biomarkers. Therefore, new treatment options and biomarkers are needed. LAM cells express melanocytic markers, including glycoprotein non-metastatic melanoma protein B (GPNMB). The function of GPNMB in LAM is currently unknown; however, GPNMB’s unique cell surface expression on tumor versus benign cells makes GPNMB a potential therapeutic target, and persistent release of its extracellular ectodomain suggests potential as a serum biomarker. Here, we establish that GPNMB expression is dependent on mTORC1 signaling, and that GPNMB regulates TSC2-null tumor cell invasion in vitro. Further, we demonstrate that GPNMB enhances TSC2-null xenograft tumor growth in vivo, and that ectodomain release is required for this xenograft growth. We also show that GPNMB’s ectodomain is released from the cell surface of TSC2-null cells by proteases ADAM10 and 17, and we identify the protease target sequence on GPNMB. Finally, we demonstrate that GPNMB’s ectodomain is present at higher levels in LAM patient serum compared to healthy controls and that ectodomain levels decrease with mTORC1 inhibition, making it a potential LAM biomarker.

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