Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes.

We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation-phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA-protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2-4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

Challenges in genomic analysis of model systems and primary tumors of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive tumor behavior and poor prognosis. Recent next-generation sequencing (NGS)-based genomic studies have provided novel treatment modes for pancreatic cancer via the identification of cancer driver variants and molecular subtypes in PDAC. Genome-wide approaches have been extended to model systems such as patient-derived xenografts (PDXs), organoids, and cell lines for pre-clinical purposes. However, the genomic characteristics vary in the model systems, which is mainly attributed to the clonal evolution of cancer cells during their construction and culture. Moreover, fundamental limitations such as low tumor cellularity and the complex tumor microenvironment of PDAC hinder the confirmation of genomic features in the primary tumor and model systems. The occurrence of these phenomena and their associated complexities may lead to false insights into the understanding of mechanisms and dynamics in tumor tissues of patients. In this review, we describe various model systems and discuss differences in the results based on genomics and transcriptomics between primary tumors and model systems. Finally, we introduce practical strategies to improve the accuracy of genomic analysis of primary tissues and model systems.