VE-cadherin junction dynamics in initial lymphatic vessels promotes lymph node metastasis

Area of Science:

• Cell Biology
• Cancer Research
• Vascular Biology

Background:

• Vascular Endothelial (VE)-cadherin regulates endothelial junction dynamics in blood and lymphatic vessels.
• VEGFA signaling plays a role in lymphatic vessel function and metastasis.

Purpose of the Study:

• To investigate how VEGFA signaling modulates lymphatic junction stability and facilitates metastasis to sentinel lymph nodes.
• To elucidate the role of VE-cadherin fragmentation in VEGFA-mediated lymphatic metastasis.

Main Methods:

• VEGFA injection in mice to induce junction zippering in dermal initial lymphatics.
• Analysis of VE-cadherin fragment shapes in lymphatic endothelium.
• Utilizing mutant mice lacking the Y949 phosphosite in VEGFR2 to assess Src kinase activation.
• Challenging mice with B16F10 melanoma and EO771 breast cancer to evaluate metastatic spread.

Main Results:

• VEGFA injection induced VE-cadherin junction zippering in dermal initial lymphatics and tumor-proximal lymphatics.
• Junctional zippering was associated with the accumulation of small, round VE-cadherin fragments.
• In mutant mice lacking the Y949 phosphosite in VEGFR2, lymphatic junction zippering occurred, but VE-cadherin fragmentation was suppressed.
• Tumor cell entry into lymphatic vessels and subsequent metastasis to lymph nodes were reduced in mutant mice compared to wild-type mice.

Conclusions:

• VEGFA mediates VE-cadherin junction zippering in initial lymphatics.
• VEGFA-induced Src kinase activation leads to increased VE-cadherin fragmentation, correlating with tumor dissemination to sentinel lymph nodes.