PI: Vera Krymskaya, Phd, MBA
Institution: University of Pennsylvania
Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive and often fatal lung disease affecting almost exclusively women of childbearing age. LAM manifests by growth of tumor-like LAM cells throughout the lung leading to destruction of lung structure. These pathological changes induce lung collapses and progressive inability to breath. We demonstrated that STAT3 is activated in LAM lungs. In this study we found that STAT3 transcriptional activity is persistently activated in the absence of any stimuli in TSC2-deficient cells. Furthermore, proinflammatory cytokine IL-6 dramatically increase STAT3 activation, suggesting that loss of TSC2 hypersensitize cellular responses to proinflammatory stimuli. In our in vivo experiments using mouse model of LAM, we demonstrated marked inhibition of LAM-like lung lesions in animals treated with STAT3 inhibitor. Furthermore, inhibition of STAT3 significantly reduced destruction of lungs in mouse model of LAM.
This translational study demonstrates a role of STAT3 activation in LAM using LAM tissue samples and LAM-derived cells. Additionally, using our newly developed unique mouse model of LAM we demonstrated that inhibition of STAT3 signaling holds a promise as a potential target to treat LAM. Collectively, our study demonstrates that STAT3 activation could serve as adjuvant biomarker of LAM as well as being molecular target for LAM treatment, which bring us one step closer towards an ultimate goal to find a cure for LAM in our lifetime.