Lesion prurigo nodularis as a risk for skin cancer

This blog highlights a case study [1] using single-cell RNA sequencing (scRNA-seq) to investigate associations between prurigo nodularis (PN) and skin cancer risk, featuring insights via BioTuring‘s  BBrowserX and Talk2Data platforms. A mini-webinar is available on the BioTuring Team’s channel.

What is prurigo nodularis?

PN is a chronic inflammatory skin condition characterized by intensely itchy and raised nodules on the skin. This condition can severely impact an individual’s quality of life. While the exact causes of PN are not fully understood, it is frequently linked to various underlying diseases.

Why fibroblasts?

Current PN treatments primarily target immune cell pathways, with limited research on other cell types like fibroblasts. Periostin (POSTN)-expressing fibroblasts play a key role in tissue regeneration processes including wound healing. Consequently, studying fibroblasts and their related genes could uncover potential targets for novel PN therapies.

Single-cell data analysis with BBrowserX and Talk2Data

Step 1. Cell Type Annotation:

The scRNA-seq dataset comprises 28,695 cells from lesional and non-lesional skin biopsies of PN patients. Cell clustering identifies major cell types, including fibroblasts (FB), keratinocytes (KC), endothelial cells (EC), lymphatic endothelial cells (LEC), smooth muscle cells (SMC), pericytes, neurons, myeloid cells, mast cells, NK T cells, and B cells (Figure 1).

Step 2. Cellular Composition:

Subclustering of fibroblasts reveals its subtype populations (Figure 2), with a notable increase in the FB1 subtype in lesional samples, indicating dynamic changes in fibroblast subtypes associated with lesion formation in PN.

Step 3. Differential Expression Analysis:

The significance of the FB1 subtype is further examined through differential gene expression analysis, revealing an upregulation of collagen synthesis genes in lesional samples (Figure 3). This enrichment of collagen-associated genes correlates with fibrous tissue overgrowth that contributes to itchy nodule formation. Additionally, POSTN, a key gene in wound healing, exhibits elevated expression in lesions. Differentially expressed genes in the FB1 subtype are relevant to extracellular matrix function and angiogenesis, both critical to wound healing in lesional areas.

Step 4. Gene Query:

Skin squamous cell carcinoma is a common type of skin cancer that prominently expresses the top differentiated expressed genes found in lesions but not in non-lesions (Figure 4).

Step 5. Pathway Analysis:

Lesions in PN are associated with oncogenic pathways absent in non-lesional samples. Pathway enrichment analysis of lesional samples highlights links to metastatic cancer, particularly involving the periostin signaling pathway (Figure 5), with POSTN promoting stemness crucial to tumor development.

Step 6. Enrichment Analysis:

Stratifying lesions by severity shows that more severe PN cases have higher enrichment of oncogenic pathway genes (Figure 6), suggesting cancer risk may rise with lesion severity.

Through this exploratory analysis, targeting fibroblasts, especially the POSTN-expressing FB1 subtype, in PN lesions emerges as a promising therapeutic strategy to mitigate cancer risk.

Beyond skin cancer with Talk2Data

BioTuring’s Talk2Data platform enables exploring the associations between PN and other diseases by analyzing high-expression genes in PN lesions. This tool helps researchers gain data-driven insights to improve treatment and monitoring strategies.

References:

1. JR Patel et al. (2024) Single-cell RNA sequencing reveals dysregulated POSTN+WNT5A+ fibroblast subclusters in prurigo nodularis. Journal of Investigative Dermatology 144, 1568-1578; doi:10.1016/j.jid.2023.12.021.

2. https://www.wikipathways.org/pathways/WP3678.html

3. https://www.gsea-msigdb.org/gsea/msigdb/human/genesets.jsp?collection=CGN