Single-Cell Transcriptomic Analysis Identifies a Novel OLR1⁺ SLC7A7⁺ Liver-Enriched Metastatic Subset With...

Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally lethal malignancy, with high percents of patients presenting with liver metastases (LM). However, the mechanisms driving liver metastases remain critical bottlenecks requiring urgent exploration.

To identify the key cellular subsets driving PDAC liver metastases, elucidate their interactions with the metastatic microenvironment, and define the underlying mechanisms of liver colonization.

Integrated single-cell transcriptomic analysis was performed using scRNA-seq data of PT and LM. The expression of signature genes within the identified cell subset was validated using clinical samples from PDAC PT and LM patients. Furthermore, ligand-receptor network analysis was conducted between the specific tumor cell subset and key immune cells.

We identified a novel liver-enriched metastatic subset (LEMS), a terminally differentiated malignant cell subpopulation characterized by metabolic reprogramming and hyperactivation of immunosuppressive pathways. We further validated the LEMS signature genes, oxidized low-density lipoprotein receptor 1 (OLR1) and solute carrier family 7 member 7 (SLC7A7), as potential diagnostic biomarkers for liver metastases. Importantly, we found that SPP1⁺ macrophages interacted with LEMS via ligand-receptor networks, thereby driving invasion and immune evasion.

We revealed the highly malignant features of LEMS and crosstalk between LEMS and SPP1⁺ macrophages in liver metastases. However, it is necessary to expand clinical cohorts and in vivo models to comprehensively elucidate the specific mechanistic interactions between LEMS and macrophages.

We delineated LEMS as an enriched subset in LM and proposed targeting of LEMS-SPP1⁺ macrophage interactions as a therapeutic strategy to disrupt metastatic progression.