Abstract B119: LY6D identifies persistent tumor-initiating cells driving pancreatic tumorigenesis

Abstract 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 Kras G12D 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. Citation Format: Juanjuan Shi, Yingying Tang, Zhengyan Zhang, Xian Wang, Shixin Meng, Ping Lu, Junyi Xu, Zheng Wang, Yongwei Sun, Jing Xue. LY6D identifies persistent tumor-initiating cells driving pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B119.