Single-cell RNA sequencing reveals intratumoral heterogeneity and potential mechanisms of malignant progression in prostate cancer with perineural invasion

Abstract

Background: Prostate cancer (PCa) is the second most common cancer among men worldwide. Perineural invasion (PNI) was a prominent characteristic of PCa, which was recognized as a key factor in promoting PCa progression. As a complex and heterogeneous disease, its true condition is difficult to explain thoroughly with conventional bulk RNA sequencing. Thus, an improved understanding of PNI-PCa progression at the single-cell level is needed.Methods: In this study, we performed scRNAseq on tumor tissues of three PNI-PCa patients. Principal component analysis (PCA) and Uniform manifold approximation and projection (UMAP) were used to reduce dimensionality and visualize the cellular composition of tumor tissues. The differently expressed genes among each cluster were identified by EdgeR. GO enrichment analysis was used to understand the roles of genes within the clusters. Pseudotime cell trajectory was used to reveal the molecular pathways underlying cell fate decisions and identify genes whose expression changed as the cells underwent transition. We applied CellPhoneDB to identify cell-cell interactions among the epithelial and neural cells in PNI-PCa.Results: Analysis of the ∼17,000 single-cell transcriptomes in three PNI prostate cancer tissues, we identified 12 major cell clusters, including neural cells and two epithelial subtypes with different expression profiles. We found that basal/intermediate epithelial cell subtypes highly expressed PCa progression-related genes, including PIGR, MMP7, and AGR2. Pseudotime trajectory analysis showed that luminal epithelial cells could be the initiating cells and transition to based/intermediate cells. Gene ontology (GO) enrichment analysis showed that pathways related to cancer progressions, such as lipid catabolic and fatty acid metabolic processes, were significantly enriched in basal/intermediate cells. Our analysis also suggested that basal/intermediate cells communicate closely with neural cells played a potential role in PNI-PCa progression.Conclusion: These results provide our understanding of PNI-PCa cellular heterogeneity and characterize the potential role of basal/intermediate cells in the PNI-PCa progression.

Unveiling novel insights in prostate cancer through single-cell RNA sequencing

“…They discovered that basal/intermediate cells showed high expression of antigen processing and presentation genes (20), specifically expressing HLA class II and the chemokine gene CCL2, which could enhance the immune response against tumor cells and potentially contribute to better survival. Additionally, basal/intermediate cells involved in perineural invasion (PNI) were found to have significant communication with neural cells through the CXCL and CCL signaling networks (22). This communication was identified as a critical factor in promoting cancer progression and metastasis in PNI-PCa (22).…”

“…Additionally, basal/intermediate cells involved in perineural invasion (PNI) were found to have significant communication with neural cells through the CXCL and CCL signaling networks (22). This communication was identified as a critical factor in promoting cancer progression and metastasis in PNI-PCa (22). Furthermore, a separate study involving primary tumor tissues from 14 untreated PCa patients reported that the epithelial subcluster with the highest number of cycling cells exhibited the highest epithelial-tomesenchymal transition (EMT) score, indicating greater tumor ecosystem diversity, which was associated with a poorer prognosis (23).…”