{
  "abstract": "Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterised by remarkable cellular heterogeneity, which emerges early from the interplay of oncogenic KRAS signalling and inflammatory injury. However, the transcriptional, metabolic and functional properties of these pre-malignant cell states that initiate and drive PDAC progression remain elusive.Objective This study aimed to identify and functionally characterise the critical premalignant cell states that arise from this heterogeneity, to define novel biomarkers and targets for early intervention.Design Public and in-house scRNA-seq data of pancreatic tumour models were analysed to identify key subpopulations in early cellular heterogeneity. Genetic perturbation in KrasG12D-driven models was performed to assess functional impact. Mechanistic studies used TurboID proximity proteomics, epigenetic profiling and metabolic assays. Clinical relevance was validated in human PDAC cohorts.Results We identified LY6D as a marker of a distinct, gastric-like cell state that emerges early and persists throughout tumourigenesis. The LY6D + population exhibits conserved stemness and a unique, pan-stage dependency on oxidative phosphorylation (OXPHOS). Genetic ablation of Ly6d specifically impaired the gastric lineage and delayed tumourigenesis, while its overexpression enhanced tumourigenic and metastatic potential. Mechanistically, the glycosylphosphatidylinositol (GPI)-anchored LY6D protein scaffolds a lipid raft-associated kinase network that drives FOSL1-dependent epigenetic-transcriptional reprogramming. In human PDAC, LY6D+ cells harbour stemness and Epithelial-Mesenchymal Transition (EMT) signatures, and high LY6D expression is an independent prognostic marker of poor survival.Conclusion Our work defines the LY6D + gastric-like cell state as a key driver linking early pre-malignant heterogeneity to PDAC initiation and progression. LY6D represents a pan-stage therapeutic target and a candidate biomarker for early detection and therapeutic targeting.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Juanjuan Shi"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Xian Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Yingying Tang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Shixin Meng"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Zhengyan Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Ping Lu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Junyi Xu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Feier Yu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China"
      ],
      "name": "Xueni Wang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China"
      ],
      "name": "Zheng Wang"
    },
    {
      "affiliations": [
        "Department of Biliary and Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Yongwei Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Systems Medicine for Cancer, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Jing Xue"
    }
  ],
  "title": "LY6D identifies persistent stem-like cells driving pancreatic tumourigenesis",
  "uid": "92844400-2046-53ba-9c7e-9ffd20575209"
}