The incidence of pancreatic ductal adenocarcinoma (PDAC) rises sharply with age, yet the specific transcriptomic adaptations of tumor epithelial cells adapted to the aging host microenvironment remain poorly understood. Identifying age-associated changes in tumor heterogeneity is critical for developing targeted therapies for older patients. Here, we constructed a comprehensive single-cell transcriptomic atlas of treatment-naïve PDAC, comparing tumor ecosystems of younger (< 65 years) and older (≥ 65 years) patients. We identified a distinct malignant ductal population characterized by high expression of the glucose transporter SLC2A1, which is preferentially expanded in the older tumor microenvironment. These SLC2A1 + ductal cells are associated with an aggressive epithelial–mesenchymal transition (EMT) program. Mechanistically, we identified YY1 as a key transcriptional regulator of this population, with YY1 expression being elevated in older patients and positively regulating SLC2A1. Functional validation in PDAC cell lines confirmed that the YY1-SLC2A1 axis contributes to the mesenchymal phenotype and invasive capacity. Clinically, a gene expression signature derived from SLC2A1 + ductal cells stratifies patient prognosis. These findings identify a metabolic EMT program driven by YY1 as a potential mechanism linking aging to tumor aggressiveness, suggesting that targeting the YY1-SLC2A1 axis may offer a therapeutic strategy for older patients with PDAC.
Wang et al. (Fri,) studied this question.