Abstract 112: ROR1 drives tumor-initiating cells in pancreatic cancer

Abstract Tumor-initiating cells are key players in driving chemoresistance and metastasis, making them promising targets for cancer therapy. However, the identity of tumor-imitating cells and molecular mechanisms underlying their capacity in human pancreatic ductal adenocarcinoma (PDAC) remains unclear. To address this, we conducted single-cell RNA sequencing and functional studies in human PDAC xenografts to identify targetable tumor-initiating cells. We found that a subpopulation characterized by a partial epithelial-mesenchymal transition (EMT)-like signature and high expression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) serves as the origin of intratumor heterogeneity in PDAC. Functional analyses demonstrated that ROR1high cells have high tumorigenicity and ROR1 promotes tumor growth, relapse following chemotherapy, and metastasis. We also showed that ROR1 prevents PDAC progression. Mechanistically, ROR1 activates the E2F transcriptional network via c-Myc, accelerating tumor cell hyperproliferation by inducing Aurora kinase B (AURKB). Moreover, epigenomic analyses revealed that ROR1 expression is flexibly controlled by the enhancer through the YAP/BRD4 axis. Targeting this pathway with a BET inhibitor effectively downregulated ROR1 expression and suppressed PDAC organoid growth. Collectively, our findings implicate ROR1high cells as tumor-initiating cells in PDAC and illuminate the therapeutic potential of ROR1 as a promising strategy for PDAC. Citation Format: Masaya Yamazaki, Takatsugu Ishimoto. ROR1 drives tumor-initiating cells in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 112.