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Manisha Taya Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Maria de la Luz Garcia-Hernandez Division of Allergy/Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Javier Rangel-Moreno Division of Allergy/Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Briaunna Minor Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Erin Gibbons Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Stephen R Hammes Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Chronic inflammation promotes progression of many cancers, with circulating myeloid-derived suppressor cell (MDSC) levels correlating with poor prognosis. Here we examine effects of MDSCs on lymphangioleiomyomatosis (LAM), a rare disease occurring almost exclusively in women whereby estrogen-sensitive metastatic TSC2-null tumors grow throughout the lungs, markedly reducing pulmonary function. The LAM cell origin remains unknown; however, previous work demonstrated that Tsc2 inactivation in the mouse uterus induced estrogen-dependent myometrial tumors with nearly all features of LAM. Half of these animals developed metastatic myometrial tumors in the lungs, suggesting that LAM cells might originate from the myometrium, possibly explaining its overwhelming female prevalence and estrogen-sensitivity. Here we report that MDSC levels, and in particular granulocytic myeloid cell levels, are elevated in the periphery and in tumors of uterine-specific Tsc2-null mice. Importantly, MDSC depletion or inhibition of their recruitment impairs myometrial tumor growth. RNA and protein analysis of Tsc2-null myometrial tumors and xenografts demonstrate high expression and activity of the serine protease neutrophil elastase (NE), with selective qPCR studies indicating a stromal origin of the NE. Notably, treatment with sivelestat, a known NE inhibitor already approved for human use in some countries, reduces tumor growth similar to MDSC depletion. Furthermore, NE promotes Tsc2-null tumor cell growth, migration, and invasion in vitro. Finally, NE-expressing myeloid cells are present throughout the lungs of LAM patients but not controls. These data suggest that NE derived from granulocytic myeloid cells might directly promote LAM tumor cell progression and could be a novel therapeutic target for LAM.

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Hen Prizant Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Manisha Taya Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Irina Lerman Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Allison Light Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Aritro Sen Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Soumya Mitra Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA

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Thomas H Foster Department of Imaging Sciences, University of Rochester Medical Center, Rochester, New York, USA

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Stephen R Hammes Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester Medical Center, Rochester, New York, USA

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Abstract

Lymphangioleiomyomatosis (LAM) is a rare disease in women. Patients with LAM develop metastatic smooth-muscle cell adenomas within the lungs, resulting in reduced pulmonary function. LAM cells contain mutations in tuberous sclerosis genes (TSC1 or TSC2), leading to up-regulation of mTORC1 activity and elevated proliferation. The origin of LAM cells remains unknown; however, inactivation of Tsc2 gene in the mouse uterus resulted in myometrial tumors exhibiting LAM features, and approximately 50% of animals developed metastatic myometrial lung tumors. This suggests that LAM tumors might originate from the uterine myometrium, possibly explaining the overwhelming prevalence of LAM in female. Here, we demonstrate that mouse Tsc2-null myometrial tumors exhibit nearly all the features of LAM, including mTORC1/S6K activation, as well as expression of melanocytic markers and matrix metalloproteinases (MMPs). Estrogen ablation reduces S6K signaling and results in Tsc2-null myometrial tumor regression. Thus, even without TSC2, estradiol is required to maintain tumors and mTORC1/S6K signaling. Additionally, we find that MMP-2 and -9, as well as neutrophil elastase (NE), are overexpressed in Tsc2-null myometrial tumors in an estrogen-dependent fashion. In vivo fluorescent imaging using MMP- or NE-sensitive optical biomarkers confirms that protease activity is specific to myometrial tumors. Similar to LAM cells, uterine Tsc2-null myometrial cells also overexpress melanocytic markers in an estrogen-dependent fashion. Finally, we identify glycoprotein NMB (GPNMB) as a melanocytic marker up-regulated in Tsc2-null mouse uteri and human LAM samples. Our data highlight the potential importance of estradiol in LAM cells, suggesting that anti-estrogen therapy may be a treatment modality. Furthermore, proteases and GPNMB might be useful LAM biomarkers.

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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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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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