Pro-Tumorigenic Role of Neutrophil Elastase in Lymphangioleiomyomatosis (LAM)

Abstract Lymphangioleiomyomatosis (LAM) is an estrogen-sensitive lung disease found almost exclusively in women. LAM characterized by the hyperproliferation of smooth muscle cells creating small tumors throughout lungs, resulting formation large cysts that replace normal alveolar space. Growth these and progression cyst development leads to loss pulmonary function, sometimes subsequent transplantation. tumor contain mutations one tuberous sclerosis genes (TSC1 or TSC2), leading activation mTORC1 pathway. In fact, mTOR inhibitors are commonly used treat LAM; however, drugs not always effective have significant side effects, suggesting need for new therapeutic targets. Additionally, recur even after transplantation circulating body fluids, a metastatic nature LAM, question origin cell. Due LAM’s estrogen sensitivity, female specificity, nature, we previously proposed originate from uterine myometrium. We therefore designed uterine-specific TSC2-null mouse model where all mice generate characteristic half develop metastases. Using RNASeq analysis tissue this model, when focusing on regulated TSC2, discovered upregulation inflammatory proteases such as Neutrophil Elastase (NE). NE secreted myeloid polymorphonuclear (PMNs) has been reported promote invasion, migration, proliferation various cancers. be true well, depleting with antibody directed against PMNs, inhibiting inhibitor, sivelestat, markedly decreased growth. released PMNs undergo Extracellular Trap release, NETosis. NETosis shown pro-tumorigenic role cancers investigating effects LAM. also generated novel background no determine whether burden metastases reduced NE-null if capable undergoing absence NE. Overall, our results suggest release critical may target its treatment.