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The transcriptional landscape analysis of basal cell carcinomas reveals novel signalling pathways and actionable
Ivan V Litvinov1, Pingxing Xie2, Scott Gunn2
1Division of Dermatology, Department of Medicine, McGill University, Montreal, Canada ivan.litvinov@mcgill.ca.
Abstract:
Basal cell carcinoma (BCC) is the most common skin cancer and human malignancy. Although most BCCs are easily managed, some are aggressive locally, require Mohs micrographic surgery, or can even metastasize. In the latter, resistance to Sonic Hedgehog inhibitors may occur. Despite their frequent occurrence in clinical practice, their transcriptional landscape remains poorly understood. By analyzing BCC RNA sequencing data according to clinically important features (all BCCs versus normal skin, high-risk versus low-risk BCCs based solely on histopathological subtypes with aggressive features, advanced versus non-advanced BCCs, and vismodegib-resistant versus vismodegib-sensitive tumors), we have identified novel differentially regulated genes and new targetable pathways implicated in BCC tumorigenesis. Pathways as diverse as IL-17, TLR, Akt/PI3K, cadherins, integrins, PDGF, and Wnt/β-catenin are promising therapeutic avenues for local and systemic agents in managing this common malignancy, including through drug re-purposing of existing medications. We experimentally validated several of these targets as biomarkers in our patient-derived cohort of primary BCC tumors.
Insights
This study deciphers the gene expression of basal cell carcinoma (BCC), revealing new therapeutic targets for this common skin cancer. Findings offer novel pathways for managing aggressive and resistant BCC tumors.
Area of Science:
- Oncology
- Dermatology
- Genomics
Background:
- Basal cell carcinoma (BCC) is the most common human malignancy, with most cases manageable but some exhibiting aggressive local behavior, metastasis, or resistance to therapies like Sonic Hedgehog inhibitors.
- The transcriptional landscape of BCC remains incompletely understood, hindering the development of targeted treatments for advanced or resistant forms of this prevalent skin cancer.
Purpose of the Study:
- To identify novel differentially regulated genes and targetable pathways in basal cell carcinoma (BCC) by analyzing RNA sequencing data.
- To explore potential therapeutic avenues for BCC, including drug repurposing, by understanding its transcriptional landscape in relation to clinical features.
- To validate identified targets as potential biomarkers in patient-derived BCC tumors.
Main Methods:
- Analysis of basal cell carcinoma (BCC) RNA sequencing data stratified by clinical features: all BCCs vs. normal skin, high-risk vs. low-risk BCCs, advanced vs. non-advanced BCCs, and vismodegib-resistant vs. vismodegib-sensitive tumors.
- Identification of differentially regulated genes and pathways implicated in BCC tumorigenesis.
- Experimental validation of selected targets as biomarkers in a patient-derived cohort of primary BCC tumors.
Main Results:
- Novel differentially regulated genes and targetable pathways were identified in BCC.
- Key pathways implicated in BCC tumorigenesis include IL-17, TLR, Akt/PI3K, cadherins, integrins, PDGF, and Wnt/β-catenin.
- Several identified targets were experimentally validated as biomarkers in patient-derived BCC tumors.
Conclusions:
- The transcriptional landscape analysis provides new insights into BCC tumorigenesis.
- Identified pathways represent promising therapeutic avenues for managing BCC, including potential for drug repurposing.
- Validated targets offer potential as biomarkers for BCC management.
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