Lymphatic Malformations with Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix
Biorxiv : the Preprint Server for Biology
|April 16, 2025
Summary
Activating KRAS mutations cause lymphatic malformations by upregulating matrix metalloproteinases (MMPs), which degrade lymphatic valve extracellular matrix, preventing proper valve formation and leading to disease.
Area of Science:
- Vascular Biology
- Molecular Genetics
- Developmental Biology
Background:
- Lymphatic malformations (LMs) result from genetic mutations affecting lymphatic vasculature.
- Activating KRAS mutations are linked to LM complications like lymphedema and chylothorax.
- The mechanism of valve loss in KRAS-mutated LMs remains unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying lymphatic valve loss in the context of KRAS mutations.
- To investigate the role of KRAS signaling in lymphatic valve development and maintenance.
Main Methods:
- Utilized a mouse model with lymphatic-specific, inducible KRAS-G12D expression and a Prox1GFP reporter.
- Analyzed human dermal lymphatic endothelial cells (hdLECs) with KRAS-G12D expression using molecular and biochemical assays.
- Performed mechanistic studies in 3D collagen matrices and tested MMP inhibitors in vivo.
Main Results:
- Lymphatic KRAS-G12D expression impaired valve development in multiple tissues.
- KRAS-G12D upregulated the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs) in hdLECs.
- MMPs degraded the extracellular matrix (ECM) core of lymphatic valves, and MMP inhibition rescued valve development.
Conclusions:
- Hyperactive KRAS signaling drives LM pathogenesis by upregulating MMPs.
- Excessive MMP activation, fueled by the PA pathway, leads to lymphatic valve ECM degradation.
- This degradation mechanism prevents lymphatic valve formation, contributing to LM phenotypes.
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