CDC42-effector interaction inhibitors alter patterns of vessel arborization in skin and tumors in vivo

Area of Science:

• Molecular Biology
• Oncology
• Dermatology

Background:

• Melanoma growth beyond 1mm requires vascularization, but current anti-angiogenesis therapies are ineffective for skin tumors.
• The specific mechanisms regulating skin tumor vascularization remain poorly understood.

Purpose of the Study:

• To identify key regulators of skin vessel arborization and explore novel therapeutic targets for melanoma.
• To evaluate the efficacy of targeting CDC42 GTPase RhoJ in inhibiting tumor vascularization and growth.

Main Methods:

• Integrated antibody infusion, optical tissue clearing, multiphoton imaging, and vessel tracing in mouse skin and vascular organoids.
• Utilized CDC42 interaction inhibitors (targeting RhoJ and CDC42) and CASIN (targeting only CDC42).
• Assessed inhibition of vessel branching, melanoma tumor vascularization, and tumor growth.

Main Results:

• RhoJ was identified as a critical regulator of skin vessel arborization.
• Small molecules targeting both RhoJ and CDC42 inhibited vessel branching in vivo and in vitro.
• These inhibitors effectively blocked melanoma tumor vascularization and reduced tumor growth, comparable to Braf inhibitors.
• The anti-vascular effects extended beyond skin, demonstrating broad applicability.

Conclusions:

• Small molecules targeting RhoJ are identified as selective tumor anti-vascular agents.
• RhoJ-targeting drugs demonstrate a strong capacity for blocking skin vascularization.
• These findings nominate RhoJ-targeting drugs as potential new treatments for melanoma and inflammatory/vascular skin diseases.