Vuong Linh M, Hachey Stephanie, Shiu Jessica, Xie Danny F, Salvador Noel, Brindani Nicoletta, Bertozzi Sine Mandrup, Summa Maria, Bertorelli Rosalia, Armirotti Andrea, Pham Rachel, Ku Vance S H, Limbekar Swara D, Nguyen Terry, Choi Bernard, Hughes Christopher C W, De Vivo Marco, Ganesan Anand K
Department of Dermatology, University of California, Irvine, Irvine 92697, CA, USA.
Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine 92697, CA, USA.
iScience. 2025 Jul 14;28(7):112971. doi: 10.1016/j.isci.2025.112971. eCollection 2025 Jul 18.
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 and vascular organoids . 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.
皮肤肿瘤需要血管供应才能生长至深度超过1毫米，但现有的抗血管生成药物在治疗皮肤中出现的黑色素瘤肿瘤方面大多无效。通过整合抗体注入、光学组织透明化、多光子成像和血管追踪的方法，我们确定了CDC42 GTP酶RhoJ是皮肤血管分支的关键调节因子。靶向RhoJ和CDC42的小分子（CDC42相互作用抑制剂），而非仅靶向CDC42的小分子（CASIN），可抑制小鼠皮肤和血管类器官中的血管分支。这种抗血管作用并不局限于皮肤，因为CDC42相互作用抑制剂可阻断黑色素瘤肿瘤血管生成，并抑制肿瘤生长，其程度与Braf抑制剂相似。综上所述，这项研究确定了靶向RhoJ的小分子作为选择性肿瘤抗血管药物。靶向RhoJ的药物对阻断皮肤血管生成具有特殊倾向，有望成为炎症性/血管性皮肤病的新疗法。
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