Age-associated changes in type I collagen promote the invasion of BRAFV600E mutated melanoma cells and their resistance to targeted therapies within three-dimensional matrix models
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引用次数: 0
Abstract
Melanoma represents the most aggressive form of skin cancer, with the highest rate of mortality. Anti-mutated BRAFV600E therapies, such as vemurafenib, has improved the prognosis for melanoma patients; however, resistance to these targeted therapies frequently emerges. Type I collagen—a key element of the tumor microenvironment—contributes to tumor progression and therapeutic resistance. With aging, type I collagen undergoes structural remodeling that alters its fibrillar organization and mechanical properties. Although these changes have been documented, their impact on BRAFV600E-mutated melanoma cell behavior and drug response remains unclear. In this study, we utilized both in vitro and in vivo models to fill this critical gap by investigating how collagen remodeling associated with advanced age modulates BRAFV600E-mutated melanoma response to vemurafenib. Our findings indicate that in vitro—using a 3D culture matrix model—old collagen promotes increased proliferation of 1205Lu cells and protects both 1205Lu and SKMEL28 cells from vemurafenib effects. This was associated with elevated YAP expression, suggesting a role for mechanotransduction in drug resistance. The 3D collagen matrix spheroid model revealed that aged collagen enhances the invasive properties of 1205Lu cells, which correlated with an upregulation of the AXL receptor. In vivo, vemurafenib reduced tumor growth in athymic mice xenografted with melanoma cells embedded in young collagen matrices, but not in those with aged collagen. Collectively, our data suggest that age-related alterations in type I collagen contribute to reduced efficacy of anti-BRAFV600E therapies in BRAFV600E-mutated melanoma.
期刊介绍:
Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.