A Novel Perspective on Genes Driving Metastatic Pancreatic Cancer Revealed by Single-cell RNA Sequencing

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is formidable in its advanced, metastatic stage. Aggressive spread of malignant cells from the pancreas to distant organs like the liver and lungs is often detected late, complicating treatment by markedly limiting therapeutic options and worsening prognosis by drastically diminishing survival. Understanding the molecular intricacies driving metastasis is crucial for developing targeted therapies for this deadly disease with otherwise narrow recourse. Method: We obtained single-cell transcriptomes (GSE154778) from the website of the United States National Institutes of Health. The single-cell RNA profiles of 10 PDAC primary tumors and six metastatic lesions, dissociated from one another, were obtained using the 10x Genomics Chromium platform. Our analysis focused on identifying genes, pathways, and gene ontology terms with distinct expression patterns between metastatic and primary single cells. Results: Through single-cell RNA-sequencing (RNA-seq), we discerned significant alterations in gene expression profiles between primary tumors and metastatic lesions in PDAC, particularly emphasizing the dysregulation of ribosomal protein (RP) gene family as potential drivers of aggressive cancer behavior. Moreover, the enrichment of pathways related to metabolism, hypoxia response, and microbial influences underscores the intricate interplay between cellular adaptations and the tumor microenvironment in facilitating metastasis. Conversely, the downregulation of signaling pathways and extracellular matrix remodeling suggests a loss of regulatory control and enhanced invasive potential in metastatic cells. Conclusions: In our comparison of primary and metastatic PDAC using single-cell RNA-seq, we have identified numerous differentially expressed genes, pathways, and gene ontology terms. The most significant finding may be that the ribosomal protein (RP) gene family is shared by 48 of the top 50 overexpressed pathways (comprising 5,848 genes), meaning that altering any member of this family as a potential driver could affect 48 pathways simultaneously. This revelation that metastatic cells may be regressed to a non-metastatic state by downregulating the RP gene family presents a promising pathway since this family is druggable.