Abstract 3067: The long non-coding RNA CDH3-AS1 facilitates gemcitabine resistance and lung metastasis via TGFβ activation in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with chemotherapy serving as the primary treatment for PDAC when surgery is not feasible. Gemcitabine is commonly used as the first-line chemotherapeutic agent in PDAC treatment, yet resistance to gemcitabine frequently emerges, necessitating the development of novel strategies to improve its efficacy. In our study, we established a gemcitabine resistant PDAC cell model through an evolutionary process involving gradually increasing gemcitabine concentrations. RNA-Seq analysis revealed significant upregulation of extracellular matrix (ECM) signaling in resistant cells. ECM dysregulation impeded gemcitabine uptake, leading to resistance. In addition, resistant cells showed reduced proliferation compared to parental cells, further exacerbating resistance. Mechanically, we found enhanced activation of the transforming growth factor β (TGFβ) pathway in resistant cells, resulting in increased expression of ECM-related genes and cyclin kinase Inhibitor p57. Moreover, we found that the long non-coding RNA (LncRNA) CDH3-AS1, the antisense of CDH3, was significantly upregulated in resistant cells and exhibited a positive correlation with ECM signaling in SMAD4 mutant PDAC, suggesting its role as a regulator of TGFβ signaling. Disrupting CDH3-AS1 impaired TGFβ activation in resistant cells by inhibiting TGFBR1 and SMAD4, thereby reversing gemcitabine resistance. Interestingly, CDH3-AS1 also regulated the expression of CDH3 in resistant cells, promoting lung metastasis through mediating epithelial-to-mesenchymal transition (EMT). The study reveals CDH3-AS1 as a novel regulator of TGFβ activation that contributes to PDAC progression, providing a new potential therapeutic target for the treatment of this aggressive cancer. Citation Format: Mengli Yang, Rui Wang, Haijian Sun, Ming Dong, Qiang Chen. The long non-coding RNA CDH3-AS1 facilitates gemcitabine resistance and lung metastasis via TGFβ activation in pancreatic ductal adenocarcinoma [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 3067.