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Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.

Lorenzo M Fernandes1, Jeffrey Tresemer1, Jing Zhang2

  • 1Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, United States.

Frontiers in Cell and Developmental Biology
|October 16, 2023
PubMed
Summary

Activating KRAS mutations cause complex lymphatic anomalies (CLAs) by disrupting lymphatic endothelial cell (LEC) development. MEK1/2 inhibition with trametinib shows promise for treating CLAs by restoring normal lymphatic vessel formation.

Keywords:
Gorham-Stout diseaseKRAScomplex lymphatic anomalylymphangiogenesislymphatic malformationtrametinib

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Area of Science:

  • Vascular biology
  • Developmental biology
  • Molecular genetics

Background:

  • Complex lymphatic anomalies (CLAs) are rare diseases stemming from lymphatic vessel maldevelopment.
  • Somatic activating mutations in KRAS are implicated in CLA pathogenesis.
  • The precise mechanisms linking KRAS mutations to CLAs remain unclear.

Purpose of the Study:

  • To elucidate the role of KRAS signaling in lymphatic endothelial cell (LEC) function and lymphatic development.
  • To investigate the therapeutic potential of targeting the MAPK pathway in KRAS-driven CLAs.

Main Methods:

  • Expression of KRASG12D in embryonic lymphatic endothelial cells (LECs) and primary human LECs.
  • Assessment of LEC morphology, proliferation, migration, and gene expression.
  • Pharmacological inhibition of MEK1/2 using trametinib in vitro and in vivo.
  • Analysis of lymphatic vessel formation and hyperplasia in embryonic models.

Main Results:

  • KRASG12D expression in LECs impairs lymphovenous valve formation, enlarges lymphatic vessels, and alters LEC behavior (spindling, proliferation, migration).
  • KRASG12D increases AKT and ERK1/2 phosphorylation and downregulates maturation-associated genes.
  • Trametinib treatment reverses KRASG12D-induced changes, reduces ERK1/2 phosphorylation, and upregulates maturation genes.
  • MEK1/2 inhibition suppresses KRASG12D-induced lymphatic hyperplasia in embryonic models.

Conclusions:

  • Tight regulation of KRAS/MAPK signaling is crucial for proper lymphatic vessel development during embryogenesis.
  • MEK1/2 inhibition represents a potential therapeutic strategy for CLAs caused by activating KRAS mutations.