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Lookup NU author(s): Dr Lee BorthwickORCiD, Professor Andrew FisherORCiD
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Copyright ©The authors 2026. For reproduction rights and permissions contact permissions@ersnet.org.RATIONALE: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease driven by nodules containing TSC2-/- "LAM cells" and recruited LAM-associated fibroblasts. Although rapamycin reduces lung function loss, some patients continue to decline, meaning additional therapies are needed. OBJECTIVES: To investigate how the LAM nodule environment affects LAM cell proliferation and the response to rapamycin. METHODS: Proteins altered in advanced LAM were identified using shotgun proteomics and immunohistochemistry in tissue from closely phenotyped patients. Genes associated with rapamycin insensitivity on LAM derived extracellular matrix were identified by RNA sequencing and validated using pharmacological inhibitors. RESULTS: More advanced disease was associated a greater decline in forced expiratory volume in 1 s when treated with rapamycin (p=0.005). In advanced LAM, using proteomics analysis, an upregulation of protein clusters comprising extracellular matrix, glucose metabolism and the actin cytoskeleton was identified. RNA sequencing and immunohistochemistry confirmed expression of collagens I and VI in LAM-associated fibroblasts and LAM nodules, and increased markers of collagen turnover in patient serum (p=0.0048). Growth of LAM patient-derived cells in vitro was faster on LAM associated fibroblast-derived extracellular matrix (p<0.0001) and incompletely suppressed by rapamycin. RNA sequencing identified upregulation of pathways driving cell cycle control, transcription and metabolism by extracellular matrix. Tractable, pro-proliferative, upregulated genes included CDK7, GAS6, PLAUR and PLAU. Inhibitors of these pathways reduced LAM cell proliferation and enhanced the antiproliferative effect of rapamycin. CONCLUSIONS: Extracellular matrix deposition upregulates the expression of genes which may blunt the response to rapamycin, but offer additional therapeutic opportunities for patients with established LAM.
Author(s): Clements D, Babaei-Jadidi R, Johnson J, Miller S, Shah N, Sand JMB, Leeming DJ, Borthwick LA, Fisher AJ, Dufour A, Johnson SR
Publication type: Article
Publication status: Published
Journal: The European Respiratory Journal
Year: 2026
Volume: 67
Issue: 5
Online publication date: 21/05/2026
Acceptance date: 15/11/2025
ISSN (print): 0903-1936
ISSN (electronic): 1399-3003
Publisher: European Respiratory Society
URL: https://doi.org/10.1183/13993003.00492-2025
DOI: 10.1183/13993003.00492-2025
PubMed id: 41381226
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