Exploring glucocorticoid receptor signaling in lymphangioleiomyomatosis

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) signaling 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 toward 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 ACTH and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiologic 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 signaling may contribute to aspects of LAM cell behavior and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.

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Journal
ERJ Open Research
Published
2026-01-22
DOI
https://doi.org/10.1183/23120541.01285-2025
Primary Topic
Tuberous Sclerosis Complex Research
Type
article
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article

Exploring glucocorticoid receptor signaling in lymphangioleiomyomatosis

Luis Gómez-Carrera, C Valenzuela, Hazel Hunt, Charlotte Sefton et al.
ERJ Open Research
Tuberous Sclerosis Complex Research
article

Exploring glucocorticoid receptor signaling in lymphangioleiomyomatosis

Luis Gómez-Carrera, C Valenzuela, Hazel Hunt, Charlotte Sefton, Guillermo P. Vicent, Adriana Rozy, X Matias-Guiu, María Lorena Molina-Molina, Debbie Clements, Calvin S. Leung, Carmen Herranz, Alexandra Baiges, Paulina Skronska, Dominik Jung, Julie S. Di Martino, José Antonio Rodríguez-Portal, Hagen S. Bachmann, Irène Garcia, Katarzyna Błasińska, Álvaro Casanova, Rosario T. Sanz, David Monk, Julio Ancochea, Adam White, Elzbieta Janina Radzikowska, Arzoo Shabbir, Lara Ruiz-Auladell, Eva Revilla-López, Manel Esteller, Jacobo Sellares, Miguel Angel Pavón, Antonio Gómez, Elizabeth P. Henske, Simon R. Johnson, Miquel Angel Pujana, Elias J. Bou-Farhat, Jonathan Adams, Ramón Manuel Lago-Lestón, Francesca Mateo, Clara Salas, Laura Muinelo-Romay, Leanne Walker, Suzanne Miller, Xavier Farré, Mercè Donate, Yan Tang, Raúl Rigo-Bonnin, Roderic Espín, David Kwiatkowski, Marina K. Holz
article en

Abstract

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) signaling 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 toward 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 ACTH and cortisol levels, together with reduced 17-hydroxyprogesterone, compared with controls. In a prospective cohort, ACTH levels were suggestively associated with advanced radiologic 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 signaling may contribute to aspects of LAM cell behavior and disease status. Further investigation of this pathway could clarify its role as a disease modifier and potential therapeutic target.

ERJ Open Research
University of East Anglia (GB), University of North Carolina at Chapel Hill (US), Universitat de Vic - Universitat Central de Catalunya (ES), Hebron University (PS), Brigham and Women's Hospital (US), Witten/Herdecke University (DE), New York Medical College (US), Universidad Francisco de Vitoria (ES), Brown University (US), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), Hospital Universitari Arnau de Vilanova (ES), University of Manchester (GB), Masih Daneshvari Hospital (IR), Institut d'Investigació Biomédica de Bellvitge (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Institut Català d'Oncologia (ES), Institut d'Investigació Biomèdica de Girona (ES), Hospital Clínic de Barcelona (ES), National Center for Tuberculosis and Lung Disease (GE), Vall d'Hebron Hospital Universitari (ES), Hospital Universitario de La Princesa (ES), Instituto de Biomedicina de Sevilla (ES), Instituto de Investigación Biomédica de Lleida (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Biomedical Research Institute (US), Nottingham Biomedical Research Centre (GB), Heron Therapeutics (United States) (US), Instituto de Investigación Sanitaria de Santiago (ES), Hospital Universitario del Henares (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Institut de Biologia Molecular de Barcelona (ES)
Good health and well-being
Openalex Percentile: Top 81%
Tuberous Sclerosis Complex Research
DOIOpen Access PDFOpenAlex
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