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.

Public Health Relevance

Lymphangioleiomyomatosis (LAM) is a devastating progressive lung disease that occurs almost exclusively in women and is characterized by smooth muscle cell tumors grow within the lungs, often leading pulmonary failure. Our laboratory has recently developed a mouse model for LAM, demonstrating that LAM lung tumors actually originate from the uterus and require estrogen for growth and survival. This proposal will use our mouse model to study how estrogen regulates LAM progression, with the ultimate goal to discover novel approaches that we can use to treat this debilitating disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA193583-02
Application #
9189693
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Sathyamoorthy, Neeraja
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Prizant, Hen; Taya, Manisha; Lerman, Irina et al. (2016) Estrogen maintains myometrial tumors in a lymphangioleiomyomatosis model. Endocr Relat Cancer 23:265-80
Prizant, Hen; Hammes, Stephen R (2016) Minireview: Lymphangioleiomyomatosis (LAM): The "Other" Steroid-Sensitive Cancer. Endocrinology 157:3374-83