Abstract SY25-01: NEAT1 long-noncoding RNA controls nuclear phase condensates that suppress ferroptosis in cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor patient outcomes, often due to the development of drug resistance. Shifts in tumor cell transcriptional subtypes from well-differentiated classical to aggressive basal-like cells can drive chemotherapeutic resistance. Such transcriptomic changes have also been linked to cellular metabolic states, but how these gene expression programs are mediated at the molecular level remains unclear. The stress-responsive long non-coding RNA NEAT1, an essential constituent of nuclear phase condensates called paraspeckles, has been associated with classical PDAC and was also previously linked to regulation of cellular metabolism. In this study, we utilized a high throughput drug screening approach in NEAT1-deficient cancer cells to uncover functional metabolic targets in these cells, identifying ferroptosis via GPX4 inhibition as a major vulnerability. We find that the paraspeckle-forming isoform of NEAT1 is central to ferroptosis suppression and extend these results into PDAC cell line models with genetic suppression and activation of NEAT1. NEAT1-nucleated paraspeckles functionally underlie the classical PDAC subtype and control an expression program tied to ferroptosis resistance. CRISPRa/i mediated transcriptional up- or down-regulation of NEAT1 paraspeckles confers ferroptosis resistance or sensitivity, respectively. We identify the paraspeckle suppressive RNA-binding protein QKI, associated with basal-like PDAC, as a positive regulator of ferroptosis susceptibility upstream of NEAT1. These results link NEAT1 and regulation of paraspeckle condensates to ferroptosis susceptibility in PDAC and offer specific avenues for targeting metabolic vulnerabilities dependent on the presence or absence of paraspeckles in pancreatic cancer cells. Citation Format: Dakarai Esgdaille, Zamira Guerra Soares, Krista Pipho, Fabio Hecht Castro Medeiros, Sara Blick-Nitko, Isaac S. Harris, Stephano S. Mello, Paul L. Boutz. NEAT1 long-noncoding RNA controls nuclear phase condensates that suppress ferroptosis in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SY25-01.