Molecular Biomarkers in pathogenesis of Lymphangioleiomyomatosis (LAM)

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Project Summary Lymphangioleiomyomatosis (LAM) is a progressive lung disease which can lead to respiratory failure and potential death. LAM is treated with drugs targeting the mammalian target of rapamycin (mTOR) pathway however, only a subset of patients responds to the treatment which is transient and not curative. Interestingly, there are numerous studies which have suggested that other pathways are important in the pathogenesis of the disease. Our laboratory has demonstrated that high mobility group HMGA2, a non-histone chromosomal architectural transcription factor, is critical in the pathogenesis of LAM. Published studies from our group demonstrate that HMGA2 is required for the mesenchymal tumorigenesis in the tuberous sclerosis (Tsc2+/-) mouse model. We therefore hypothesize that the HMGA2 signaling pathway drives the pathogenesis of tumors initiated in the TSC2 haploinsufficiency state in LAM. Furthermore, we postulate that the expression of HMGA2 and its oncogenic pathway genes can be used clinically for LAM diagnosis and potential prognosis. To test our hypotheses, we propose the following objectives: In the first aim our studies we will test the hypothesis that fluxes in expression of HMGA2 pathway targets can be used as indices of LAM disease occurrence and severity. In the second aim of the study, we will further delineate the role of the HMGA2 pathway in the disease of LAM by determining if genetic and pharmacological disruption of the HMGA2 pathway disrupts growth and tumor formation in human iPS cells from LAM patients.