CDC42 Inhibitors Alter Patterns of Vessel Arborization in Skin and Tumors in vivo
CDC42 Inhibitors Alter Patterns of Vessel Arborization in Skin and Tumors in vivo
Abstract Tumors that arise in the epidermis must develop a vascular supply to grow beyond a millimeter in depth. This process requires CDC42 GTPases such as CDC42, RhoJ and RhoQ. Despite this dependence on angiogenesis for growth, melanoma tumors are minimally responsive to current anti-angiogenesis agents, highlighting the need for more effective drugs in this class. Here we integrate antibody infusion, optical tissue clearing, multiphoton imaging, and three-dimensional semi-automated tracing to develop a quantitative approach to measure changes in vascular architecture in skin and skin tumors. This new approach uncovered differences in vessel arborization in the skin of RhoJ KO mice as compared to wild-type mice. Furthermore, novel small molecules that inhibit CDC42 GTPases inhibited both tumor growth and vessel branching within tumors to a similar degree as Braf inhibitors, which are commonly used to treat melanoma. In contrast to Braf inhibitors, however, which only affected tumor vasculature, CDC42 inhibitors affected vascularization in both tumor and normal skin without apparent toxicity to endothelial or stromal cells. These novel CDC42 inhibitors similarly blocked vessel branching in human cell-based micro-physiological models of normal and tumor vessels. RNA sequencing revealed reduced expression of multiple angiogenesis-related genes in drug-treated skin. Taken together, these studies identify a new class of pharmacologic agents that inhibit vessel branching in both normal skin and tumors with potential utility for treating skin cancer and skin diseases characterized by pathologic angiogenesis.
De Vivo Marco、Ganesan Anand K、Shiu Jessica、Xie Danny F、Bertozzi Sine Mandrup、Armirotti Andrea、Pham Rachel、Ku Vance SH、Nguyen Terry、Choi Bernard、Hughes Christopher CW、Bertorelli Rosalia、Salvador Noel、Hachey Stephanie、Vuong Linh M、Brindani Nicoletta、Summa Maria
Molecular Modeling and Drug Discovery LabDepartment of Dermatology, University of CaliforniaDepartment of Dermatology, University of CaliforniaBeckman Laser Institute and Medical Clinic, University of CaliforniaAnalytical Chemistry FacilityAnalytical Chemistry FacilityDepartment of Dermatology, University of CaliforniaDepartment of Dermatology, University of CaliforniaDepartment of Dermatology, University of CaliforniaBeckman Laser Institute and Medical Clinic, University of CaliforniaDepartment of Molecular Biology and Biochemistry, University of CaliforniaTranslational Pharmacology FacilityDepartment of Biological Chemistry, University of CaliforniaDepartment of Molecular Biology and Biochemistry, University of CaliforniaDepartment of Dermatology, University of CaliforniaMolecular Modeling and Drug Discovery LabTranslational Pharmacology Facility
医学研究方法肿瘤学基础医学
De Vivo Marco,Ganesan Anand K,Shiu Jessica,Xie Danny F,Bertozzi Sine Mandrup,Armirotti Andrea,Pham Rachel,Ku Vance SH,Nguyen Terry,Choi Bernard,Hughes Christopher CW,Bertorelli Rosalia,Salvador Noel,Hachey Stephanie,Vuong Linh M,Brindani Nicoletta,Summa Maria.CDC42 Inhibitors Alter Patterns of Vessel Arborization in Skin and Tumors in vivo[EB/OL].(2025-03-28)[2025-05-14].https://www.biorxiv.org/content/10.1101/2024.04.09.588609.点此复制
评论