Inhibition of endothelial FAK activity prevents tumor metastasis by enhancing barrier function

Area of Science:

• Oncology
• Cell Biology
• Vascular Biology

Background:

• Focal adhesion kinase (FAK) plays a role in tumor growth and metastasis.
• Endothelial cells (ECs) are crucial in the metastatic process.
• Vascular endothelial cadherin (VEC) is involved in endothelial cell barrier function.

Purpose of the Study:

• To investigate the role of FAK in tumor-associated endothelial cells (ECs).
• To identify specific targets of FAK in ECs relevant to metastasis.
• To determine if FAK inhibition in ECs can prevent tumor metastasis.

Main Methods:

• Utilized conditional kinase-dead FAK knockin mice in ECs.
• Investigated vascular endothelial growth factor (VEGF-A) and tumor-induced VEC phosphorylation.
• Examined the effects of FAK inhibition and VEC mutations on EC permeability and tumor cell transmigration.
• Assessed tumor cell extravasation and metastasis in vivo.

Main Results:

• FAK inhibition in ECs prevented VEC-Y658 phosphorylation, a key event in endothelial barrier regulation.
• FAK inhibition and VEC-Y658F mutation blocked VEGF-initiated paracellular permeability and tumor cell transmigration.
• EC FAK inhibition suppressed VEGF-dependent tumor cell extravasation and melanoma lung metastasis.
• Primary tumor growth was unaffected by EC FAK inhibition.

Conclusions:

• Endothelial cell FAK is a critical regulator of endothelial barrier function and tumor metastasis.
• FAK acts downstream of c-Src in regulating EC barrier integrity.
• Targeting EC FAK presents a potential strategy to inhibit cancer metastasis without affecting primary tumor growth.