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Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include human melanoma black-45\u2013positive epithelioid cells and smooth muscle \u03b1-actin\u2013expressing 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 coexpressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D coculture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared with non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming rapamycin. We also verified tuberous sclerosis complex 2\u2013deficient renal angiomyolipoma (TSC2-null AML) cells as key VEGF-A secretors; VEGF-A was suppressed by sorafenib in both TSC2-null AML cells and LAMFs. These findings highlight VEGF-A and basic FGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.<\/jats:p>","DOI":"10.1172\/jci.insight.187899","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T12:01:51Z","timestamp":1738670511000},"source":"Crossref","is-referenced-by-count":10,"title":["Targeting fibroblast\u2013endothelial cell interactions in LAM pathogenesis using 3D spheroid models and spatial transcriptomics"],"prefix":"10.1172","volume":"10","author":[{"given":"Sinem","family":"Koc-Gunel","sequence":"first","affiliation":[{"name":"Hastings Center for Pulmonary Research; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine; and"},{"name":"Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California, USA."},{"name":"Department of Internal Medicine II, Infectious Diseases, and"},{"name":"Institute for Medical Virology, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily C.","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6606-4408","authenticated-orcid":true,"given":"Lalit K.","family":"Gautam","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben A.","family":"Calvert","sequence":"additional","affiliation":[{"name":"Hastings Center for Pulmonary Research; 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