Exploring glucocorticoid receptor signalling in lymphangioleiomyomatosis

Area of Science:

• Endocrinology
• Oncology
• Pulmonology

Background:

• Lymphangioleiomyomatosis (LAM) is a rare neoplasm causing progressive lung destruction, often linked with renal angiomyolipomas (AMLs).
• Evidence suggests a connection between LAM risk and pulmonary traits.
• The role of glucocorticoid receptor (GR) signaling in LAM biology and clinical features was investigated.

Purpose of the Study:

• To investigate the influence of glucocorticoid receptor (GR) signaling on lymphangioleiomyomatosis (LAM) biology and clinical features.
• To explore GR signaling as a potential therapeutic target for LAM and associated renal angiomyolipomas (AMLs).

Main Methods:

• Cell-based studies using murine and human TSC2-deficient cells.
• Glucocorticoid receptor (GR) inhibition/activation assays and gene expression analysis.
• Single-cell RNA sequencing, hormone profiling in LAM cohorts, and association with clinical variables.

Main Results:

• GR activation in LAM/AML models induced transcriptional responses, while GR inhibition reduced clonogenic potential.
• GR stimulation upregulated CDKN1C, promoting slower proliferation and differentiation-prone states.
• Altered hormone profiles in women with LAM, including elevated ACTH and cortisol, and suggestive association of ACTH with advanced disease stage.

Conclusions:

• Glucocorticoid receptor (GR) signaling appears to influence lymphangioleiomyomatosis (LAM) cell behavior and disease status.
• The GR signaling pathway represents a potential disease modifier and therapeutic target for LAM.
• Further research into GR signaling is warranted to clarify its role in LAM pathogenesis.