TGFß signaling in the pathogenesis of lymphangioleiomyomatosis

RESEARCH SUMMARY Lymphangioleiomyomatosis (LAM) is a debilitating, progressive lung disease for which few therapeutic options are available because of a lack mechanistic knowledge of the pathogenesis. The hallmark of LAM is the formation of neoplastic lesions (nodules) composed of smooth muscle-like epithelioid-like cells (LAM cells), followed by destruction of lung tissue and invasion of both bronchioles and lymphatic vessels. LAM cells are enveloped by lymphatic endothelial cells (LECs) and interact with activated LAM fibroblasts (LAMFs), which resemble carcinoma-associated fibroblasts. A critical knowledge gap is how interactions among these cell types drive LAM pathogenesis, and filling this gap will be key to developing effective treatments for LAM. Our long-term goal is to contribute to the design of new therapies for LAM by identifying candidate targets. The objective of the proposed research is to identify the cellular mechanisms that govern functional changes in the cell populations that contribute to pulmonary dysfunction in LAM. Our central hypothesis, based on the literature and our strong preliminary data, is that intercellular signaling within LAM nodules is dependent on TGF-β signaling and inhibition of the mTOR pathway, and it contributes to the hallmarks of LAM: fibroblast activation, endothelial-cell recruitment, and alveolar simplification. We will test the ability of changes TGF-β signaling in LAM-cells to contribute to LAM pathogenesis by activating surrounding fibroblasts, dysregulating differentiation of the alveolar epithelium, and promoting the growth and migration of cells within LAM nodules. To this end, we will engineer novel, multicellular 3-D organoid and lung-on-chip models that will enable us to test the effects of TGF-β signaling on the growth of LAM nodules, and to identify mechanisms that drive both this growth and alveolar simplification. We will do so by determining the extent to which LAM-cell dependent upregulation of TGF-β signaling drives disease-associated phenotypic changes in lung fibroblasts and lymphatic endothelial cells (Aim 1); and defining the cellular interactions that govern TGF-β signaling in TSC2 mutation-associated LAM and their impact on the differentiation of alveolar cells (Aim 2). This study will be possible because of our unique access to non-diseased and LAM-patient tissues and cells, as well as to immortalized cell lines derived from renal angiomyolipoma (AML) of LAM origin. The expected outcomes are (1) a novel and reproducible 3D culture system in which TSC2-null (and control) cells are co-cultured with both primary human lung fibroblasts and transitional alveolar cells, as well as LAM-chips produced from these, which will enable the study of LAM onset, and (2) knowledge of mechanisms by which TGF-β signaling and mTOR inhibition contribute to LAM pathogenesis. These outcomes put us in an excellent position to pursue support for future studies designed to understand the intercellular signaling that leads to LAM initiation and progression and to screen for therapeutic approaches that impact aspects of disease progression in the multiple cell types involved. Project Number: 1R21HL184612-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Amy Ryan | Institution: UNIVERSITY OF IOWA, IOWA CITY, IA | Award Amount: $233,250 | Activity Code: R21 | Study Section: Pulmonary Injury, Repair, and Remodeling Study Section (PIRR)[PIRR] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HL18461201