Tracking Pancreatic Ductal Adenocarcinoma Orgin Using Single Cell RNA Sequencing Data

Abstract

Objectives: To investigate the cellular origin of human pancreatic ductal adenocarcinoma (PDAC) on single-cell RNA sequencing (scRNA-seq) data. Introduction: PDAC is one of the most lethal cancers with the lack of early diagnosis and limited response to treatment. Identification of the cell of origin has an important role in new preventive therapeutic approaches to suppress or reverse the initial phase of carcinogenesis. Acinar, ductal, islet or progenitor cells have been hypothesized as the cellular origin of PDAC. However, there is no direct evidence confirming the hypotheses. Methods: In this study, data for single-cell RNA sequencing platform 10X Genomics integration from human PDAC were downloaded from the Genome Sequence Archive (GSA) database with accession number PRJCA001063, which comprised 28 samples, including 21 primary PDAC samples and 7 control pancreas samples. To preprocess the reads, the Cell Ranger (v7.1.0) and Seurat (v4.3.0) pipeline were utilized, employing default and recommended parameters. To investigate the cellular origin of PDAC, a comprehensive analysis of pseudotime trajectory was conducted using the Slingshot and Monocle methods relying on the analysis of differential gene expression (DGE) profiles, copy number variation (CNV), and single nucleotide variants (SNV). Results: A subgroup of ductal cells with progenitor characteristics, referred to as progenitor-like ductal cells (PLDCs), was identified through clustering analysis. Both slingshot and monocle analysis consistently demonstrated that cluster 05, representing PLDCs, served as the starting point for all trajectories in the pseudotime analysis. The trajectory inferences revealed two distinct transition axes leading to the differentiation of PLDCs into ductal and acinar cells. Additionally, these findings unveiled the sharing of PLDCs among PDAC cell populations, despite their high heterogeneity. Conclusions: Our analysis suggests that the PLDCs (progenitor-like ductal cells) serve as the cell of origin of PDAC.