AXL promotes lymphangiogenesis by amplifying VEGF-C-mediated AKT pathway

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Lymphangiogenesis, the formation of new lymphatic vessels, is crucial for cancer metastasis.
• Understanding lymphangiogenesis within lymph nodes is key to developing anti-metastasis strategies.
• The role of specific molecular pathways in lymph node lymphangiogenesis remains an active area of research.

Purpose of the Study:

• To investigate the previously unrecognized role of the tyrosine kinase receptor AXL in lymphatic vessel formation.
• To elucidate the molecular mechanisms by which AXL influences lymphangiogenesis within lymph nodes.
• To identify potential therapeutic targets for inhibiting cancer metastasis through modulation of lymphangiogenesis.

Main Methods:

• Validated AXL expression in lymphatic endothelial cells (LECs).
• Utilized RNA interference and pharmacological inhibition (R428/Bemcentinib) to study AXL function.
• Investigated AXL activation by Vascular Endothelial Growth Factor C (VEGF-C) and downstream AKT signaling.
• Assessed AXL's role in vivo using a VEGF-C-induced lymphangiogenesis model in lymph nodes.

Main Results:

• AXL significantly promotes LEC migration in 2D and 3D cultures.
• AXL activation is induced by VEGF-C and signals through the AKT pathway.
• Pharmacological inhibition of AXL reduced lymphangiogenesis in vivo.
• AXL is predominantly expressed in MARCO+ LECs, with increased density and penetration under metastatic conditions.

Conclusions:

• AXL is a potent enhancer of lymphangiogenesis, operating via the VEGF-C/AKT signaling axis.
• AXL expression in a specific LEC subpopulation (MARCO+) is linked to metastatic conditions.
• Targeting AXL presents a potential strategy to inhibit metastasis by disrupting lymph node lymphangiogenesis.