小鼠皮肤早期基底细胞癌的转录组分析：激光剥脱分段激光和维莫德吉比的局部治疗效果对比

Transcriptomic Analysis of Early-Stage Basal Cell Carcinomas in Murine Skin Following Topical Treatments With Ablative Fractional Laser and Vismodegib

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EXPERIMENTAL DERMATOLOGY

影响因子:3.1

分区:医学3区 / 皮肤病学2区

发表日期:2024 Oct

作者: Kristian Kåber Pedersen, Merete Hædersdal, Uffe Høgh Olesen, Thomas Litman

DOI: 10.1111/exd.15187

摘要

近期研究表明，激光剥脱分段激光（AFL）可以抑制hedgehog通路、增强免疫浸润，并清除小鼠模型中的基底细胞癌（BCC）。本研究采用RNA测序，进一步分析AFL对含有早期显微BCC的小鼠皮肤转录组的影响，并与局部应用hedgehog抑制剂维莫德吉比的效果进行对比。结果显示，小鼠皮肤中BCC的诱导主要与基因上调相关（显著上调基因：277，显著下调基因：24）。通过Ingenuity Pathway Analysis对这些基因的特征分析表明，肿瘤诱导与BCC和Sonic Hedgehog信号通路的激活有关。AFL和维莫德吉比都逆转了这些变化，其中维莫德吉比表现优越，逆转了大部分上调基因（AFL：59/277；维莫德吉比：180/277）。令人惊讶的是，Ingenuity Pathway Analysis还显示AFL和维莫德吉比都引起了大量免疫细胞的浸润。基于基因集富集分析和细胞类型去卷积，AFL治疗导致的免疫细胞募集最大，主要包括中性粒细胞、巨噬细胞和单核细胞。总之，AFL和维莫德吉比在BCC皮肤中的不同作用提示两者存在显著差异。未来，结合AFL和维莫德吉比的免疫调节作用，可能会增强治疗效果。

Abstract

Recent studies have demonstrated that ablative fractional laser (AFL) can inhibit the hedgehog pathway, enhance immune infiltration and clear basal cell carcinomas (BCCs) in murine models. In this study, we applied RNA sequencing to further characterise the impact of AFL on the transcriptome of murine skin containing early-stage microscopic BCCs, contrasting it with the effects of topical application of the hedgehog inhibitor vismodegib. Our results showed that BCC induction in murine skin was primarily linked to gene upregulation (significantly upregulated genes: 277, significantly downregulated genes: 24). Characterisation of these genes with Ingenuity Pathway Analysis showed that tumour induction was associated with activation of BCC and Sonic Hedgehog signalling. Both AFL and vismodegib treatments reversed these changes, with vismodegib demonstrating superior performance by reversing most of the upregulated genes (AFL: 59/277; vismodegib: 180/277). Surprisingly, Ingenuity Pathway Analysis also revealed that both AFL and vismodegib treatments caused considerable immune cell infiltration. Based on gene set enrichment analysis and cell type deconvolution, AFL treatment resulted in the largest immune cell recruitment, which for both treatments primarily consisted of infiltrating neutrophils, macrophages and monocytes. In conclusion, the distinct effects observed in BCC skin following AFL and vismodegib treatment suggest key differences between the two interventions. Future applications of AFL or vismodegib treatments could leverage their individual effects, for example by combining the effect of AFL on the immune system with other topical treatments.