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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter 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
Zeitschrift JCI insight
Quellenangaben Band: 10, Heft: 6, Seiten: , Artikelnummer: e187899 Supplement: ,
Verlag Clarivate
Verlagsort Ann Arbor, Michigan
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Pioneer Campus (HPC)
Förderungen 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)