Estrogen Signaling in a Mouse Model for Lymphangioleiomyomatosis



 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a somewhat rare but devastating progressive lung disease in which adenomas consisting of immature smooth muscle cells grow within the lungs. As LAM tumors expand, patients develop pulmonary cysts, recurrent pneumothorax, and progressive pulmonary function loss, sometimes requiring lung transplantation. One difficulty in studying LAM, and therefore in developing therapeutic options, has been that the origin of the LAM cell is unknown. However, several features of LAM offer potential clues. First, LAM cells contain inactivating mutations in tumor suppressor genes Tsc1 or Tsc2, leading to increased mTORC1-mediated proliferation. Second, LAM affects almost exclusively women, with a female prevalence of over 99.95%. Third LAM progression is enhanced by estradiol. Finally, LAM lung tumors may be metastatic, as patients who have undergone lung transplantation can develop LAM tumors in transplanted lungs. To explain these LAM characteristics, we proposed that lung LAM cells might be derived from smooth muscle uterine myometrial cells lacking Tsc. In fact, when we ablated Tsc2 in the mouse uterus, we saw myometrial overgrowth, leiomyoma formation, and metastatic myometrial lung tumors. Uterine and lung tumors shared many features of LAM, including increased mTORC1 activity and positive staining for LAM markers. We also found that myometrial tumors expressed high levels and activity of matrix metalloproteinases (MMPs). Notably, tumor growth, mTORC1 activity, melanocyte differentiation marker expression, and protease expression, were almost completely dependent on estradiol, suggestive that estradiol may be a key regulator of LAM. In short, our model confirms a potential metastatic origin of LAM from the uterus, and provides a robust model for LAM. Here we will use our model to: 1) Examine mechanisms of estrogen-dependence using state-of-the art strategies for measuring estradiol, kinase, and mTORC1 signaling; 2) Examine lung damage and function using plethysmography, pulmonary function testing, and CT scanning; and 3) Examine the roles of MMPs in LAM progression as well as the utility of measuring MMP activity as a biomarker for tumor burden using protease-sensitive optical biomarkers. With our team's expertise in steroid signaling, uterine and lung biology, and protease detection, we believe that we are in a unique position to make novel discoveries that will not only help us understand and treat LAM, but will also enhance our general knowledge of how estrogen promotes tumor progression.