Raegan Myers - Graduate Student

Lymphangioleiomyomatosis (LAM) is a multisystemic genetic disease with poor outcomes associated with pulmonary manifestation primarily found in women. Over time, small thin-walled cysts reorganize the lung architecture, blocking efficient gas exchange. These cysts are made up of a collection of estrogen-sensitive smooth muscle tumor cells with mutations in tuberous sclerosis gene complex (TSC), known as LAM cells. Deleterious mutations in TSC lead to constitutive activation of mTORC1 signaling, leading to inappropriate levels of growth and proliferation of LAM cells. These characteristics led our lab to hypothesize that these tumor cells may be arising from the smooth muscle cells of the uterine myometrium. To test this our lab generated a uterine specific model by deletion of TSC2, resulting in a uterine tumor phenotype reminiscent of LAM that has metastatic to the lung.  Transcriptomic analysis of the uterine tumor microenvironment revealed differential gene expression of melanocytic markers and the serine protease neutrophil elastase (NE). The first half of my talk will be dedicated to melanocytic markers, which can be a potential biomarker for LAM, particularly glycoprotein non-metastatic melanoma protein B (GPNMB). This protein has been shown in TSC2 null cells to mediate invasion specifically through its cleavage. Additionally, tumor growth phenotypes appear to be modulated by TSC2 null cell expression of GPNMB in xenograft tumors. Currently, I am generating a mouse uterine cell line of LAM, which will be used in tandem with other TSC2 null cell lines to assess GPNMB’s role in migration, invasion, and lung colonization. The second part of this talk will focus on NE.  Previously our lab investigated the role of neutrophils in promoting tumor growth, and implicated neutrophil elastase specifically in tumor growth and the migratory capacity of TSC2 null cell lines, however we have yet to demonstrate the direct mechanism behind this phenomenon.  Our lab has generated histological evidence of NETosis in both the uterine tumor of our mouse model and in lung samples from patients with LAM, where NETosis may serve as the mechanism for NE release. Future work will explore the impacts of NETs on TSC2 null cell lines and targeting components of NETs (DNA and neutrophil serine proteases) through DNAse and DPP1 intervention. By considering both pathways, we hope to interrogate the biology of TSC2 null cells through GPNMB and inflammatory responses to TSC2 null cells through NETosis.

 Dec 18, 2025 @ 12:00 p.m.
 Medical Center | K307 (3-6408)