Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis

作者：Laura Muinelo-Romay, Leanne Walker, Elżbieta Radzikowska, María Molina-Molina, Calvin S. Leung, Jacobo Sellares, Hagen S. Bachmann, Miguel Angel Pavón, Anthony S. Zannas, Guillermo P. Vicent, Adriana Róży, Clara Salas, Marina K. Holz, Luis Gómez-Carrera, Charlotte Sefton, Alexandra Baiges, Rafael de Cid, Debbie Clements, Mercè Donate-Castillo, S. Miller, Elizabeth P Henske, José A. Rodríguez-Portal, Miquel Angel Pujana, Manel Esteller, Claudia Valenzuela, Xavier Matias-Guiu, Raúl Rigo-Bonnin, Roderic Espín, Antonio Gómez, Carmen Herranz-Ors, Eva Revilla‐López, David Monk, Xavier Farré, Anne White, Álvaro Casanova, Yan Tang, Rosario T. Sanz, Katarzyna Błasińska, Rosalía Laporta, Hazel Hunt, Francesca Mateo, Ramón Manuel Lago-Lestón, Lara Ruiz-Auladell, Dominik Jung, Piedad Ussetti, Simon R. Johnson, David Kwiatkowski, Paulina Skrońska, Julie S. Di Martino, Elias J. Bou-Farhat, Irene García, Jonathan Adams-Furmanski, Julio Ancochea, Arzoo Shabbir · 发表于：UNC Libraries · 年份：2026 · DOI：10.17615/eqvd-k206 · 研究领域：Tuberous Sclerosis Complex Research、Renal cell carcinoma treatment、Vascular Tumors and Angiosarcomas

Background: Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm that causes progressive cystic lung destruction and is often associated with renal angiomyolipomas (AMLs). Given evidence of pleiotropy linking LAM risk to pulmonary traits, we investigated whether glucocorticoid receptor (GR) signalling might influence LAM biology and clinical features. Methods: We combined cell-based studies, GR inhibition/activation assays, gene expression and single-cell RNA sequencing analyses, and hormone profiling in retrospective and prospective LAM cohorts. Cellular experiments employed murine Tsc2−/− embryonic fibroblasts and human TSC2−/− AML cells. Circulating steroid levels were measured in women with LAM and healthy controls, and associations with clinical variables were evaluated. Results: In LAM/AML models, GR activation by glucocorticoids elicited transcriptional responses, whereas GR inhibition reduced clonogenic potential. GR stimulation was associated with CDKN1C upregulation through enhancer binding, and single-cell profiling suggested a shift towards slower proliferation and differentiation-prone states enriched for a LAM cell signature. Clinically, our analyses suggest that women with LAM may show altered circulating hormone profiles, including elevated adrenocorticotropic hormone (ACTH) and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated...