Work

SUN-303 Glycoprotein non-metastatic melanoma protein B (GPNMB) mitigates TSC2 null tumor growth and metastasis in Lymphangioleiomyomatosis

Year: 2025

Type: article

Abstract: Disclosure: R. Myers: None. K. Camacho: None. T. Henson: None. M. Wines-Samuelson: None. E. Gibbons: None. S.R. Hammes: None. Lymphangioleiomyomatosis (LAM) is a multisystemic disease almost exclusively found in genetic females. Patients experience breathing complications due to the formation of cystic tumors throughout their lungs. These cysts appear to be caused by the abnormal proliferation of cells with a smooth muscle phenotype in the lungs. These tumor cells are estrogen sensitive and possess deleterious mutations in at least one of two in tuberous sclerosis (TSC1/2) complex genes, which leads to overactive mTORC signaling, dysregulated protein synthesis, and cell proliferation. LAM tumor cells appear to be metastatic, as they can be found in the blood and lymph of LAM patients and have been shown to repopulate the lungs of LAM patients who have needed lung transplantation. Our laboratory hypothesized that the origin of LAM cells is the myometrium of the uterus, leading to the generation of a uterine specific TSC2 null mouse model. These mice developed LAM lesions that metastasized from the uterus to the lungs in an estrogen-sensitive fashion. Here we describe a TSC2-null mouse myometrial cell line that was cultivated from these uterine-specific TSC2 knockout mice. These cells share nearly all characteristics of human LAM cells, including the expression of the melanocytic marker glycoprotein nonmetastatic melanoma protein B (GPNMB). Single cell RNA sequencing data on human lung samples confirm GPNMB upregulation in LAM core cells and macrophages. Notably, the extracellular domain of GPNMB can be released from the cell surface. While the role of GPNMB cleavage on LAM progression is not yet clear, we discovered that GPNMB levels are high in LAM patient serum, and are reduced with mTOR-inhibition therapy, demonstrating clinical potential of GPNMB as a biomarker for LAM. Clinical observations of high cellular expression GPNMB levels across other malignancies such as melanoma and triple negative breast cancer are associated with poor prognosis, suggesting that GPNMB may be a driver of tumor progression. In support of this hypothesis, we find that, in rat TSC2 null cells, GPNMB down-regulation slows xenograft growth, implying the necessity to explore GPNMB expression and cleavage in TSC2 null models. We provide data demonstrating how GPNMB modulates cell proliferation, migration, and invasion in our novel TSC2 null mouse myometrial cell line. We will also provide data demonstrating the important role of GPNMB cleavage in these functions. In sum, we propose that GPNMB may serve both as a biomarker for LAM as well as a potential target for the treatment of patients with LAM. Presentation: Sunday, July 13, 2025

Source: Journal of the Endocrine Society