Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease of women. Pulmonary LAM consists of a diffuse proliferation of smooth muscle actin-positive cells and increased lymphatic vessel density. LAM cells harbor inactivating mutations in either the TSC1 or TSC2 tumor suppressor gene, resulting in constitutive activation of mammalian TOR (target of rapamycin) complex 1 (mTORC1). mTORC1 integrates growth factor and nutrient signaling to stimulate cell growth and metabolism. Critical unmet needs in LAM are the development and optimization of effective therapeutic strategies and the availability of sensitive and specific biomarkers of disease progression and response to therapy, which could streamline the design, duration, and cost of early phase clinical trials. Our long-term goal is to identify mTORC1-dependent or independent metabolic vulnerabilities of LAM cells that can be targeted therapeutically in LAM. In lipidomic studies, we identified enhanced choline phospholipid metabolism in cellular models of LAM compared to control cells, and elevated phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) species in LAM patient plasma compared to healthy women. Our central hypothesis is that abnormal lipid metabolism contributes to the molecular pathogenesis of LAM and represents a source for therapeutic targets and metabolic imaging biomarkers of disease progression in LAM. This hypothesis will be tested in three Aims.
Aim 1. To identify the molecular mechanisms underlying dysregulation of choline phospholipid synthesis in LAM. Our working hypothesis is that the de novo PC synthesis and PC remodeling pathways are aberrantly activated via mTOR-dependent and independent mechanisms in TSC2-deficient cells.
Aim 2. To determine the impact of aberrant lipid metabolism on LAM cell proliferation and LAM-associated lymphangiogenesis. Our working hypothesis is that lipid and signaling modifications downstream of choline kinase or PLA2 participate in the proliferation of LAM cells and trigger lymphatic microvascular endothelial cell migration and proliferation.
Aim 3. To determine the impact of therapeutic targeting of choline phospholipid metabolism in LAM in vivo. Our working hypothesis is that aberrant lipid metabolism in LAM can be targeted therapeutically and used diagnostically. We will conduct preclinical trials of inhibitors of choline phospholipid metabolism using mouse models of LAM, [11C]choline Micro-PET (positron emission tomography) to detect in vivo changes in choline uptake of TSC2-deficient cells, and a mouse-ear model of LAM cell-associated lymphangiogenesis. The proposed studies have clinical significance because they will address the potential for key enzymes of the choline phospholipid pathway as targets in LAM therapeutics, and for [11C]choline as a metabolic imaging biomarker of disease progression and/or response to treatment in LAM patients.
Lymphangioleiomyomatosis (LAM) is a rare, multisystem disease of women, characterized by progressive cystic lung destruction and diffuse proliferation of TSC2-deficient cells with hyperactive mTORC1. We identified aberrant choline phospholipid metabolism in cellular models of LAM and elevated choline-containing phospholipids in LAM patient plasma compared to healthy women. Our goal is to address the potential for key enzymes of the choline phospholipid pathway in LAM therapeutics, and for choline-PET imaging in the monitoring of disease progression and/or response to treatment in LAM.
|Filippakis, Harilaos; Alesi, Nicola; Ogorek, Barbara et al. (2017) Lysosomal regulation of cholesterol homeostasis in tuberous sclerosis complex is mediated via NPC1 and LDL-R. Oncotarget 8:38099-38112|