Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis
Year: 2026
Type: article
Abstract: 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 with advanced radiological disease stage. AML cells showed elevated expression of POMC , which encodes the precursor of ACTH, and POMC peptide was detected in LAM lung tissue. Conclusions Our findings suggest that GR signalling may contribute to aspects of LAM cell behaviour and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.
Source: ERJ Open Research
Authors: Alexandra Baiges, Lara Ruiz-Auladell, Irene García, Raúl Rigo-Bonnin, Yan Tang, Elias J. Bou-Farhat, Roderic Espín, Rosario T. Sanz, Guillermo Pablo Vicent, Mercè Donate-Castillo, Arzoo Shabbir, Jonathan Adams-Furmanski, Carmen Herranz-Ors, Rosalía Laporta, Clara Salas, Piedad Ussetti, Claudia Valenzuela, Julio Ancochea, José A. Rodríguez-Portal, María Molina-Molina, Álvaro Casanova, Eva Revilla-López, Luis Gómez-Carrera, Xavier Matias-Guiu, Miguel Angel Pavón, Dominik Jung, Hagen S. Bachmann, Ramón Manuel Lago-Lestón, Laura Muinelo-Romay, Xavier Farré, Rafael de Cid, Calvin S. Leung, Anthony S. Zannas, Manel Esteller, Jacobo Sellares, Katarzyna Błasińska, Adriana Róży, Paulina Skrońska, Antonio Gómez, Marina K. Holz, Julie S. Di Martino, David Monk, Charlotte Sefton, Leanne Walker, Anne White, Debbie Clements, Suzanne Miller, Simon R. Johnson, Hazel J. Hunt, Elizabeth P. Henske, David Kwiatkowski, Elżbieta Radzikowska, Francesca Mateo, Miquel Angel Pujana
Institutions: Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, Hospital Clínic de Barcelona, Brigham and Women's Hospital, Harvard University, Consejo Superior de Investigaciones Científicas, Institut de Biologia Molecular de Barcelona, Institut d'Investigació Biomèdica de Girona, Hospital Universitario Puerta de Hierro Majadahonda, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Bellvitge University Hospital, Universidad Francisco de Vitoria, Hospital Universitario del Henares, Vall d'Hebron Hospital Universitari, Hospital Universitario La Paz, Hospital La Paz Institute for Health Research, Universidad Autónoma de Madrid, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Instituto de Investigación Biomédica de Lleida, Centro de Investigación Biomédica en Red de Cáncer, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Witten/Herdecke University, Instituto de Investigación Sanitaria de Santiago, Universidade de Santiago de Compostela, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, University of North Carolina at Chapel Hill, Brown University, Institució Catalana de Recerca i Estudis Avançats, Josep Carreras Leukaemia Research Institute, Universitat de Barcelona, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Vic - Universitat Central de Catalunya, New York Medical College, University of East Anglia, University of Manchester, University of Nottingham, National Institute for Health and Care Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Corcept Therapeutics (United States)
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $808
Funders: Deanship of Scientific Research, King Khalid University, Howard Hughes Medical Institute, Bill and Melinda Gates Foundation, Whitehall Foundation, ACMG Foundation for Genetic and Genomic Medicine, United States - Israel Binational Agricultural Research and Development Fund, Division of Cancer Prevention, National Cancer Institute, Univerzita Karlova v Praze, Arvid Nilssons Fond, North Carolina State University, Natural Science Foundation of Jilin Province, Kræftens Bekæmpelse, Fundació la Marató de TV3, Norges Teknisk-Naturvitenskapelige Universitet, LankellyChase Foundation, Neuroendocrine Tumor Research Foundation, Wellcome Trust, Università degli Studi di Milano, Innovationsfonden, UK Research and Innovation, Ministerio de Ciencia, Innovación y Universidades, Innovative Research Group Project of the National Natural Science Foundation of China, Centres de Recerca de Catalunya, Kanazawa University, Meta, Cancer Research UK, Royal Society, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Deakin University, University of Adelaide, University of Queensland, National Natural Science Foundation of China, Generalitat de Catalunya, China Postdoctoral Science Foundation, Research Grants Council, University Grants Committee, Dalian University of Technology, Fonds Wetenschappelijk Onderzoek, Ministero della Salute, Ministerstvo Zdravotnictví Ceské Republiky, Lundbeckfonden, Korea Basic Science Institute, Korea Institute of Oriental Medicine, National Research Foundation of Korea, Natural Science Foundation of Hebei Province, KU Leuven, Tehran University of Medical Sciences and Health Services, Society of Hong Kong Scholars, Natural Science Foundation of Henan Province, Bundesamt für Lebensmittelsicherheit und Veterinärwesen, Sundhedsstyrelsen, Hebei University, Zayed University, Agentura Pro Zdravotnický Výzkum České Republiky, Novo Nordisk Fonden, Innovation and Technology Fund, Science, Technology and Innovation Commission of Shenzhen Municipality, Indian Institute of Technology Guwahati, National Institutes of Health, Yale School of Medicine, Pfizer Foundation, University of Georgia Research Foundation, Health and Medical Care Committee of the Regional Executive Board, Region Västra Götaland, Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Japan Society for the Promotion of Science, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Staatssekretariat für Bildung, Forschung und Innovation, European Regional Development Fund, Departament de Salut, Generalitat de Catalunya, National Key Research and Development Program of China, Fundamental Research Funds for the Central Universities, Humanities and Social Science Fund of Ministry of Education of China, Henan Provincial Science and Technology Research Project, National Eye Institute, National Cancer Institute, National Institute of General Medical Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Moonshot Research and Development Program, H2020 European Research Council, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases
Awards: G2452644208, Factores biológicos que determinan el cáncer de mama en mujeres portadoras de variantes patogénicas del gen BRCA1: Hacia una prevención personalizada (MiPreven), G3310192352, G4412317238, G4803095502, G5406034096, G6403661385, G6467272384, G6520503711, G6656180551, G6788809761, G6849076033, G7092949412, G7604509605, G7661758681, G8464903183, G857043349
OpenAlex ID: W7125500161
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