LY6D Identifies Persistent Tumor-Initiating Cells Driving Pancreatic Tumorigenesis [RNA-seq]

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.