Aims::
Mechanism of fibroblasts in skin melanoma (SKME) revealed by single-cell
RNA sequencing data.
Background::
SKME is responsible for more than 80% of skin-related cancer deaths. Cancer-associated
fibroblasts (CAFs) generate inflammatory factors, growth factors and extracellular matrix
proteins to facilitate cancer cell growth, metastasis, drug resistance and immune exclusion. However,
molecular mechanisms of CAFs in SKME are still lacking.
Objective::
Our goal was to reveal the role of CAFs in SKME.
Methods::
We downloaded the single-cell RNA sequencing (scRNA-seq) dataset from the Gene
Expression Omnibus (GSE215120) database. Then, the Seurat package was applied to analyze the
single-cell atlas of SKME data, and cell subsets were annotated with the CellMarker database.
The molecular mechanisms of CAFs in SKME were disclosed via differential gene expression and
enrichment analysis, Cellchat and SCENIC methods.
Results::
Using scRNA-seq data, three SKME cases were used and downscaled and clustered to
identify 11 cell subgroups and 5 CAF subsets. The enrichment of highly expressed genes among
the 5 CAF subsets suggests that cell migration-inducing hyaluronan-binding protein (CEMIP) + fibroblasts
and naked cuticle homolog 1 (NKD1) + fibroblasts were closely associated with epithelial
to mesenchymal transition. Cellchat analysis revealed that CAF subpopulations promoted melanocyte
proliferation through Jagged1 (JAG1)-Notch homolog 1 (NOTCH1), JAG1-NOTCH3
and migration through pleiotrophin (PTN)-syndecan-3 (SDC3) receptor-ligand pairs. The
SCENIC analysis identified that most of the transcription factors in each CAF subpopulation
played a certain role in the metastasis of melanoma and were highly expressed in metastatic
SKME samples. Specifically, we observed that CEMIP+ fibroblasts and NKD1+ fibroblasts had
potential roles in participating in immune therapy resistance. Collectively, we uncovered a single--
cell atlas of SKME and revealed the molecular mechanisms of CAFs in SKME development, providing
a base for immune therapy and prognosis assessment.
Conclusion::
Our study reveals that 5 CAFs in SKME have a promoting effect on melanocyte proliferation
and metastasis. More importantly, CEMIP+ fibroblasts and NKD1+ fibroblasts displayed
close connections with immune therapy resistance. These findings help provide a good basis
for future immune therapy and prognosis assessment targeting CAFs in SKME.