Meves, Alexander

ABSTRACT The recent inclusion of the Merlin clinicopathologic–gene expression profile (CP‐GEP) assay in the National Comprehensive Cancer Network (NCCN) Melanoma Guidelines represents an important milestone in the clinical integration of molecular testing for cutaneous melanoma. Unlike earlier melanoma gene expression profile (GEP) assays, which focused primarily on prognostic risk stratification, CP‐GEP was specifically developed to predict sentinel lymph node (SLN) metastasis risk by identifying early metastatic competence within primary melanomas, with additional prognostic utility. This review discusses the biological evidence supporting CP‐GEP and examines how unbiased transcriptomic discovery converged with established insights from cancer cell biology, integrin signaling, focal adhesions, and extracellular matrix (ECM) remodeling to shape its conceptual framework. We further discuss how CP‐GEP captures a transformation‐associated biological state centered on an integrin‐ and TGF‐β–dependent signaling axis ( ITGB3 , TGFBR1 ) that promotes pericellular proteolysis and ECM remodeling ( PLAT , SERPINE2 , LOXL4 ), inflammatory and angiogenic signaling ( CXCL8 , GDF15 ), and melanocytic lineage identity ( MLANA ). Collectively, these genes identify a dissemination‐competent phenotype that is detectable within primary tumors before clinically apparent metastasis. Overall, the biological framework supporting CP‐GEP reinforces the concept that altered adhesion signaling and ECM remodeling are central drivers of early melanoma metastasis and represent clinically actionable biomarkers for individualized melanoma management. image

ABSTRACT The stromal tumor environment (STE) plays a vital yet often underrecognized role in cancer progression, shaping tumor development. It influences complex interactions among stromal cells, immune cells, extracellular matrix (ECM) components, and signaling molecules. Stromal cells regulate integrin signaling and are involved in remodeling the tumor microenvironment, driving critical processes such as cell migration, survival, angiogenesis, and proliferation. Advances in understanding the STE are creating new opportunities for early cancer detection and treatment. Innovations in molecular imaging, particularly for melanoma, are transforming cancer diagnostics by providing deeper insights into tumor biology, cellular interactions, and angiogenesis, paving the way for more personalized and timely therapeutic interventions. Among these advancements, in vivo skin fluorescent imaging (SFI) stands out as a powerful tool, offering real‐time molecular insights at the point of care with the ability to improve patient management.

Summary Integrins are heterodimeric receptors important for cell adhesion and signaling. Integrin α5β1 is a key mediator of angiogenesis and its dysregulation is associated with tumor progression and metastasis. Despite numerous efforts, α5β1-targeting therapeutics have been unsuccessful due to poor efficacy and off-target effects. A contributing factor is our limited understanding of how integrin conformation influences interactions with therapeutics. Using cell-based functional assays, patient-derived xenografts, biophysics, and electron microscopy, we shed light on these relationships by characterizing two anti-α5β1 antibodies, BIIG2 and MINT1526A. We show that both antibodies bind α5β1 with nanomolar affinity, reduce tube formation in vitro , and bind overlapping epitopes that block fibronectin binding. However, using electron microscopy, we reveal that while BIIG2 binding does not substantially alter the conformational states, MINT1526A preferentially recognizes the bent conformation and restricts the conformational ensemble. These insights can guide which aspects to prioritize to improve the design of future integrin-targeted therapeutics.

AbstractBackgroundChronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time‐to‐healing of chronic wounds.MethodsA cohort of 79 patients with chronic wounds was evaluated in a single‐center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time‐to‐healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16INK4a expression.ResultsNo clinical or pathological characteristics were found to have significant associations with time‐to‐healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21CIP1/WAF1) expression to predict longer time‐to‐healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time‐to‐healing. Increased p16INK4a staining was observed in diabetic wounds compared to non‐diabetic wounds, and the same association was observed in the context of high dermal fibrosis.ConclusionsThe findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds.