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Koc-Gunel, S.* ; Liu, E.C.* ; Gautam, L.K.* ; Calvert, B.A.* ; Murthy, S.* ; Harriott, N.C.* ; Nawroth, J. ; Zhou, B.* ; Krymskaya, V.P.* ; Ryan, A.L.*

Targeting fibroblast-endothelial interactions in LAM pathogenesis using 3D spheroid models and spatial transcriptomics.

JCI insight 10:e187899 (2025)

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Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle α-actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-deficient renal angiomyolipoma cells (TSC2-null AML) as key VEGF-A secretors, which was suppressed by sorafenib in both TSC2-null AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Cell Biology ; Cell Migration/adhesion ; Genetic Diseases ; Protein Kinases ; Pulmonology; Tuberous Sclerosis Complex; Growth Factor-d; Pulmonary Lymphangioleiomyomatosis; Multikinase Inhibitor; Sorafenib; Rapamycin; Lung; Lymphangiogenesis; Management; Sirolimus

ISSN (print) / ISBN 2379-3708

e-ISSN 2379-3708

Journal JCI insight

Quellenangaben Volume: 10, Issue: 6, Article Number: e187899

Publisher Clarivate

Publishing Place Ann Arbor, Michigan

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Helmholtz Pioneer Campus (HPC)

Grants CF BOUCE19R
LAM Foundation (ALR)
German Research Foundation
German Federal Ministry of Education
NIH/National Heart, Lung, and Blood Institute
Roy J. Carver Charitable Trust
University of Iowa Carver College of Medicine
NIH
Hastings Foundation (ALR)