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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
Korrespondenzautor
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
Nichtpatentliteratur Publikationen
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)