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Characterization of Human Melanoma Skin Cancer Models: Paving the Way for Model-Based Melanoma Research and Drug Discovery

ABSTRACT: The need for advanced tissue models in medical research and drug development is more critical than ever. Recent changes in EU law to reduce animal testing and U.S. regulation allowing the FDA to approve drugs without animal trials highlight the importance of these models in advancement of medical science. For the models to be applicable in preclinical studies, it is essential that models are thoroughly characterized so as to understand their applicability and limitations to avoid misinterpretation caused by their limited replication of the biological functions. In this study, we applied bioimaging and RNA sequencing to assess and contrast the architecture and gene expression profiles of various skin models, including melanoma skin models. Our results indicate that these models closely emulate actual skin morphology and gene expression, with the full-thickness (FT) models exhibiting superior resemblance to human skin, especially in the formation of the basement membrane and cellular interactions. These characteristics make the FT model particularly useful for research that focuses on these aspects. Furthermore, the integrity of the skin-like properties and genetic signatures, of both skin and melanoma cell lines, was maintained upon integration of melanoma cells, establishing these models as robust platforms for cancer research and pharmacological development. The responsiveness of the FT melanoma models to vemurafenib was successfully monitored through live imaging, demonstrating their validity as a reliable, reproducible, and humane tool for cancer research and drug development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254491 | GEO | 2024/12/09

REPOSITORIES: GEO

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Project description:We established a model of human melanoma metastasis to identify differentially expressed genes in brain metastasis, compared to cutaneous melanoma from which they were developed. Such genes may control brain metastasis. The identification and characterization of these genes would advance the understanding of the metastatic process and may lead to new diagnostics and therapeutic approach. Brain metastases occur in almost 40% of melanoma patients. The median survival of such patients does not exceed a few months. Very little information is available on mechanisms underlying the progression of melanoma towards brain metastasis. The function, and significance of the various factors involved in melanoma progression must be deciphered using relevant models. Currently, most human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intra-cardiac administration. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, sub-dermal variants that originate from the same melanomas thus sharing a common genetic background. The brain metastasizing variants were obtained by intra-cardiac inoculation. One of the brain metastasizing variants when inoculated sub-dermally yielded spontaneous brain dormant micrometastasis. Cells from the spontaneous brain micrometastasis when removed from the brain microenvironment proliferate very well in vitro and generate tumors in the skin being the orthotopic organ site. The brain metastasis and micro-metastasis cells expressed higher levels of ANGPTL4, COX-2, MMP1, MMP2 and PRAME and lower levels of CLDN1, CYR61 and IL-6R than the cutaneous variants. These gene products may be involved in melanoma brain metastasis and may serve as novel brain metastasis biomarkers and targets for therapy. 8 Samples (arrays) were analyzed. We generated pairwise comparisons between cutaneous and brain metastatic variants of the same genetic background, using Partek Genomics Suite, in the three melanoma models. Genes with pM-bM-^IM-$5% and a fold-change difference of M-bM-^IM-%1.25 or <-1.25 were selected.

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Characterization of Human Melanoma Skin Cancer Models: Paving the Way for Model-Based Melanoma Research and Drug Discovery

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