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Transcriptomic Analysis of Early-Stage Basal Cell Carcinomas in Murine Skin Following Topical Treatments With
Kristian Kåber Pedersen1, Merete Hædersdal1, Uffe Høgh Olesen1
1Department of Dermatology, Copenhagen University Hospital - Bispebjerg, Copenhagen, Denmark.
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.
Insights
Ablative fractional laser (AFL) and vismodegib both reversed hedgehog pathway activation in basal cell carcinoma (BCC) models. AFL significantly increased immune cell infiltration, suggesting combination therapy potential.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Basal cell carcinoma (BCC) is a common skin cancer.
- The hedgehog signaling pathway is crucial in BCC development.
- Ablative fractional laser (AFL) has shown potential in treating BCCs.
Purpose of the Study:
- To compare the transcriptomic effects of AFL and vismodegib on early-stage murine BCCs.
- To investigate the impact of these treatments on gene expression and immune infiltration.
Main Methods:
- RNA sequencing was used to analyze gene expression changes in murine skin with BCCs.
- Ingenuity Pathway Analysis and gene set enrichment analysis were performed.
- Cell type deconvolution was employed to assess immune cell infiltration.
Main Results:
- BCC induction was associated with significant upregulation of 277 genes, primarily related to BCC and Sonic Hedgehog signaling.
- Both AFL and vismodegib reversed these gene expression changes.
- Vismodegib reversed more upregulated genes (180/277) than AFL (59/277).
- Both treatments induced significant immune cell infiltration, with AFL causing greater recruitment of neutrophils, macrophages, and monocytes.
Conclusions:
- AFL and vismodegib exhibit distinct molecular and immunological effects on BCC.
- AFL enhances immune cell infiltration, suggesting potential for combination therapies.
- Further research could explore combining AFL's immunomodulatory effects with other topical treatments for BCC.
