Glucocorticoid Receptor Signaling Modifies Lymphangioleiomyomatosis Cell Behavior and Disease Progression

Lymphangioleiomyomatosis (LAM) is a rare, low-grade neoplasm characterized by progressive cystic lung destruction and often associated with renal angiomyolipomas (AMLs). Current treatments are limited, and understanding underlying mechanisms is crucial. Given evidence linking LAM risk to pulmonary traits and the pleiotropic role of glucocorticoids, researchers investigated whether glucocorticoid receptor (GR) signaling influences LAM biology and clinical features, aiming to identify novel therapeutic avenues.

Researchers employed a multi-pronged approach, combining cell-based studies with GR inhibition/activation assays. Experiments utilized murine Tsc2 -/- embryonic fibroblasts and human TSC2 -/- AML cells. They performed gene expression and single-cell RNA sequencing analyses to characterize cellular responses. Additionally, hormone profiling was conducted in retrospective and prospective cohorts of women with LAM and healthy controls. Circulating steroid levels were meticulously measured, and their associations with various clinical variables were evaluated to bridge cellular findings with patient outcomes.

In both LAM and AML cellular models, glucocorticoid-mediated GR activation consistently elicited distinct transcriptional responses. Conversely, GR inhibition significantly reduced clonogenic potential, highlighting its role in cell proliferation. Specifically, GR stimulation was associated with CDKN1C upregulation, mediated through direct enhancer binding. Single-cell profiling further revealed that GR activation induced a shift towards slower proliferation and differentiation-prone states, which were notably enriched for a LAM cell signature. > Clinically, women with LAM exhibited altered circulating hormone profiles, including significantly elevated adrenocorticotropic hormone (ACTH) and cortisol levels, alongside reduced 17-hydroxyprogesterone, compared to healthy controls. In a prospective cohort, elevated ACTH levels were suggestively associated with advanced radiological disease stage. Furthermore, AML cells demonstrated elevated expression of POMC, the precursor gene for ACTH, and POMC peptide was detected within LAM lung tissue, suggesting local production.