Recent advances in CDC42 subfamily inhibition and therapeutic potential

Trends in Pharmacological Sciences · 2026-05-01

CDC42 subfamily members of the RHOGTPases exist in either an active or inactive state, each with a distinct but highly flexible structure, making them challenging to target. Abnormal CDC42 activity is linked to various conditions, including cancer, neurological and ophthalmological disorders, skin diseases, and vascular conditions. This has driven increasing interest in developing CDC42 inhibitors, which have recently produced lead compounds demonstrating disease-modifying effects in vivo. In this review, we provide an overview of the physiological functions of CDC42 subfamily members and their emerging roles in disease. We also examine the latest advances in leveraging CDC42's structural features for selective inhibition, analyzing the mode of action and chemical structures of current inhibitors. These insights aim to inform the design of improved molecules with broad therapeutic potential.

Towards label-free, two photon tissue imaging as a guide to surgery

2026-03-05

Three-dimensional imaging for facial vitiligo: Results from a phase 2 randomized controlled trial investigating upadacitinib in patients with vitiligo

Journal of Investigative Dermatology · 2026-01-01

BACKGROUND: Upadacitinib (UPA), an oral selective Jak inhibitor, showed significantly greater facial repigmentation than placebo as assessed by Facial Vitiligo Area Scoring Index (F-VASI) in a phase 2 clinical trial. A nested substudy explored a 3-dimensional (3D) imaging platform as an objective tool to quantify facial vitiligo repigmentation. METHODS: Adults with nonsegmental vitiligo received 6, 11, or 22 mg UPA or placebo for 24 weeks (period 1). For weeks 24-52 (period 2), UPA-treated patients continued UPA at assigned doses; patients receiving placebo switched to 11 or 22 mg UPA. In this substudy, efficacy was assessed by the percentage change from baseline in facial vitiligo area with 3D imaging and F-VASI. RESULTS: The substudy included 27 patients. Patients receiving UPA showed facial repigmentation at weeks 24 and 52 as assessed by 3D imaging and F-VASI. There was a high correlation between 3D imaging and F-VASI measurements at baseline (r = 0.85; P < .0001). At week 24, there was a high correlation (r = 0.71; P = .0003) between the percentage change from baseline in 3D imaging and F-VASI measurements, which diminished by week 52 (r = 0.01; P = .9600). CONCLUSIONS: 3D imaging shows potential as an objective tool for evaluating changes in facial vitiligo after UPA treatment.

Characterization of the immune microenvironment of skin cancer

2026-03-04

In vivo human skin imaging: Distinguishing cellular and fibrillar components with fluorescence lifetime microscopy

Journal of Investigative Dermatology · 2025-11-20

UV induces common cutaneous amyloid-like melanosomal protein aggregates

bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-18

Misfolding of aggregation-prone proteins underpins diseases known as proteinopathies. One of these proteins, alpha-synuclein, is a component of aggregates in neurodegenerative conditions such as Parkinson's disease. The melanosomal protein PMEL, which forms physiologic amyloid scaffold structures on which melanin is organized in melanosomes, similarly ectopically accumulates in the dermis in many forms of cutaneous hyperpigmentation. Here, we demonstrate in a wide range of common clinical pigmentary disorders, as well as in primary melanocyte and mouse models examined by molecular, proteomic, and electron microscopic tools, that melanocytic alpha-synuclein is a prominent component of intracellular protein aggregates bound to similar proteins as in Parkinson's disease, as well as melanized extracellular protein deposits. Using the Real Time Quaking-Induced Conversion Assay (RT-QuIC), we demonstrate that UV induces misfolded melanosomal proteins to self-propagate, augmenting this pathology in prion-like fashion. CUT&RUN chromatin profiling and single-cell RNA-seq demonstrate that melanocytes utilize microphthalmia-associated transcription factor (MITF)-regulated autophagy to counteract protein aggregation, identifying aggregate removal as a core function of tanning. In contrast to extracellular aggregation, impaired intracellular aggregate removal contributes to melanocyte senescence, which conversely exacerbates chronic hypopigmentation and photoaging-related discoloration. These findings identify melanosomal proteinopathy as a common contributor to melanocyte dysfunction and suggest aggregate-focused management approaches.

Uncovering minimal pathways in melanoma initiation

Nature Communications · 2025-06-26 · 1 citations

Melanomas are genetically heterogeneous, displaying mitogen-activated protein kinase mutations and homozygous loss of tumor suppressor genes. Mouse models combining such mutations produce fast-growing tumors. In contrast, rare, slow-growing tumors arise in mice combining Braf activation with heterozygous loss of Pten. Here we show that similar tumors can arise in albino mice bearing only a Braf mutation. Incidence kinetics suggest a stochastic event underlies tumorigenesis in tumors that arise with only a Braf mutation, yet de novo mutations or structural variants that could explain the incidence of most tumors could not be found. Single-cell transcriptomics of tumors identify a cell type resembling "neural crest-like" cells in human and mouse melanomas. These exist in normal mouse skin, expand upon Braf activation, and persist through serial transplantation; analyses of gene expression suggest they serve as precursors of malignant cells. This state may serve as an intermediate on a slow path to malignancy that may provide a diagnostically and therapeutically important source of cellular heterogeneity.

Label-free human skin imaging with enhanced molecular contrast via time-resolved fluorescence and advanced phasor analysis

Communications Biology · 2025-12-30

Current state-of-the-art clinical skin imaging using label-free multiphoton microscopy (MPM) faces challenges due to limited molecular specificity, which hampers the accurate characterization of skin tissues because of overlapping fluorescence signals from multiple molecular components. In this study, we present a novel approach to enhance molecular contrast in MPM clinical skin imaging by leveraging advanced strategies to effectively unmix the various endogenous fluorophores present in the skin with the performance capabilities of a recently developed imaging platform for in vivo time-resolved fluorescence imaging of human skin. By identifying phasor positions of key endogenous skin fluorophores - such as keratin, melanin, free NADH, and protein-bound NADH - we effectively perform multicomponent unmixing in different skin types and conditions, including those with varying levels of pigmentation and metabolic states. The phasor analysis allows for the mapping and quantification of individual fluorescence species and provides comprehensive insight into the dynamic changes in molecular components associated with distinct clinical conditions. This study highlights the effective use of advanced imaging and phasor analysis to improve label-free molecular contrast in clinical skin imaging, leading to advancements in future research focused on precise and timely assessments of skin conditions and monitoring of therapeutic effects.

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

iScience · 2025-07-01 · 2 citations

<h2>Summary</h2> 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 <i>in vivo</i> and vascular organoids <i>in vitro</i>. 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.

210 Anti-IL-15 treatment results in greater repigmentation in vitiligo than placebo in participants who receive phototherapy and reduces circulating terminally differentiated cytotoxic CD8 memory cells

Journal of Investigative Dermatology · 2025-11-01