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Updated: May 29, 2025

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-Gunel^1,2,3,4, Emily C Liu⁵, Lalit K Gautam⁵

¹Hastings Center for Pulmonary Research; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine; and.

|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.

Keywords:

Cell biology Cell migration/adhesion Genetic diseases Protein kinases Pulmonology

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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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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.