2. Academic Validation
  3. CDC42-effector interaction inhibitors alter patterns of vessel arborization in skin and tumors in vivo

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

  • iScience. 2025 Jul 14;28(7):112971. doi: 10.1016/j.isci.2025.112971.
Linh M Vuong 1,  Stephanie Hachey 2,  Jessica Shiu 1,  Danny F Xie 3,  Noel Salvador 4,  Nicoletta Brindani 5,  Sine Mandrup Bertozzi 6,  Maria Summa 7,  Rosalia Bertorelli 7,  Andrea Armirotti 6,  Rachel Pham 1,  Vance S H Ku 1,  Swara D Limbekar 1,  Terry Nguyen 1,  Bernard Choi 3,  Christopher C W Hughes 2,  Marco De Vivo 5,  Anand K Ganesan 1
Affiliations

Affiliations

  • 1 Department of Dermatology, University of California, Irvine, Irvine 92697, CA, USA.
  • 2 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine 92697, CA, USA.
  • 3 Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine 92697, CA, USA.
  • 4 Department of Biological Chemistry, University of California, Irvine, Irvine 92697, CA, USA.
  • 5 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
  • 6 Analytical Chemistry Facility, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
  • 7 Translational Pharmacology Facility, Istituto Italiano di Tecnologia, 16163 Genova, Italy.
PMID: 40950721 DOI: 10.1016/j.isci.2025.112971
Abstract

Skin tumors require a vascular supply to grow beyond 1 mm in depth, yet existing anti-angiogenesis agents are largely ineffective at treating melanoma tumors arising in skin. Using an approach that integrates antibody infusion, optical tissue clearing, multiphoton imaging, and vessel tracing, we identified the CDC42 GTPase RhoJ as a critical regulator of skin vessel arborization. Small molecules that target both RhoJ and CDC42 (CDC42 interaction inhibitors), but not those that target only CDC42 (CASIN), inhibit vessel branching in mouse skin in vivo and vascular organoids in vitro. This anti-vascular effect was not limited to skin, as CDC42 interaction inhibitors blocked melanoma tumor vascularization and inhibited tumor growth to a similar degree as Braf inhibitors. Taken together, this work identifies small molecules that target RhoJ as selective tumor anti-vascular agents. RhoJ-targeting drugs have a particular proclivity for blocking skin vascularization, nominating them as new treatments for inflammatory/vascular skin disease.

Keywords

cancer;; microenvironment; pharmacology.

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