GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE299nnn/GSE299488/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE299488GEOGSEfalseLY6D Identifies Persistent Tumor-Initiating Cells Driving Pancreatic Tumorigenesis [RNA-seq]Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy driven by oncogenic KRAS and inflammation-induced cellular heterogeneity, yet the mechanisms underlying tumor-initiating cells (TICs) emergence and maintenance remain unclear. Our study establishes LY6D as a marker of persistent TICs that orchestrate pancreatic cancer progression across all disease stages. Single-cell RNA sequencing of inflammation-driven PDAC models reveals that LY6D+ TICs specifically originate from KRAS-mutant acinar-to-ductal metaplasia (ADM) lesions under inflammatory conditions, maintaining conserved stemness properties and exhibiting a distinctive oxidative phosphorylation (OXPHOS) dependency throughout tumor evolution. Moreover, genetic ablation of Ly6d in KrasG12D pancreata delays tumorigenesis, while forced Ly6d expression enhances tumorigenic potential and metastatic capability. Mechanistically, LY6D-despite lacking intracellular domains-scaffolds lipid raft-associated kinase networks and FOSL1-dependent epigenetic reprogramming to establish a stable pro-tumorigenic state. Clinically, LY6D+ cells are enriched in human PDAC and exhibit conserved stemness and epithelial-mesenchymal transition (EMT) properties. Strikingly, LY6D expression levels demonstrate PDAC-restricted prognostic power. Our work defines LY6D as pan-stage TICs marker linking cellular plasticity to PDAC initiation and progression, offering new avenues for early detection and interception of this lethal malignancy.2026/04/09GSE299488GSM9039727GSM9039738GSM9039739GSM9039728GSM9039736GSM9039725GSM9039726GSM9039737GSM9039734GSM9039735GSM9039724GSM9039732GSM9039733GSM9039730GSM9039731GSM903972924247299488Mus musculus[41545197]