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A 3D Spheroid Model as a More Physiological System for Cancer-Associated Fibroblasts Differentiation and Invasion In Vitro Studies
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Targeting fibroblast-endothelial cell interactions in LAM pathogenesis using 3D spheroid models and spatial
Sinem Koc-Gunel1,2,3,4, Emily C Liu5, Lalit K Gautam5
1Hastings Center for Pulmonary Research; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine; and.
JCI Insight
|February 4, 2025
Summary
This study reveals that targeting kinase pathways with multikinase inhibitors like sorafenib can reduce invasion in lymphangioleiomyomatosis (LAM), offering a promising new therapeutic strategy for this progressive lung disease.
Area of Science:
- Pulmonary Medicine
- Oncology
- Cell Biology
Background:
- Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease with poorly understood pathogenesis.
- LAM involves invasion by lymphatic endothelial cells (LECs) into clusters of epithelioid cells and LAM-associated fibroblasts (LAMFs).
- LAMFs share similarities with cancer-associated fibroblasts, and their interaction with LECs drives disease progression.
Purpose of the Study:
- To investigate the molecular mechanisms underlying LAM pathogenesis, focusing on LAMF-LEC interactions.
- To identify potential therapeutic targets and strategies for treating LAM.
Main Methods:
- Spatial transcriptomics analysis of LAM lung tissues.
- Kinase array analysis of LAMFs.
- 3D coculture spheroid model using primary LAMFs and LECs.
- In vitro drug sensitivity testing with sorafenib and rapamycin.
Main Results:
- Spatial transcriptomics identified a gene cluster enriched in kinase signaling pathways coexpressed with LEC markers in LAM tissues.
- Kinase arrays showed elevated PDGFR and FGFR in LAMFs.
- LAMF-LEC spheroids exhibited increased invasion compared to non-LAM fibroblast controls.
- Sorafenib, a multikinase inhibitor, significantly reduced spheroid invasion and suppressed VEGF-A secretion in LAMFs and TSC2-null AML cells.
Conclusions:
- VEGF-A and basic FGF signaling are implicated in LAM pathogenesis.
- Multikinase inhibition, exemplified by sorafenib, shows therapeutic potential for LAM by targeting key invasive mechanisms.
- Further research into VEGF-A and FGF pathways could lead to novel LAM treatments.
