Abstract 2798: Long non-coding RNA DUXAP10 regulates mediators of endoplasmic reticulum stress-induced epithelial-to-mesenchymal transition in anaplastic thyroid cancer

Abstract Anaplastic Thyroid Cancer (ATC) is a fast-growing, metastatic and lethal carcinoma with mortality rates reaching ∼100%. Understanding the molecular landscape that separates ATC from other slow-growing, highly survivable thyroid carcinoma subtypes is key to biomarker detection, therapeutic successes, and increased patient survival. Long non-coding RNAs (lncRNA) use their extensive DNA, RNA, and protein-binding domains to orchestrate cell function. These multi-ranged regulatory capabilities make their study in ATC salient. LncRNA DUXAP10 is overexpressed in NCBI GEO datasets by 40-fold and 20-fold (GSE33630, GSE85457) in ATC patient tissue and primary ATC cell lines compared to normal thyroid tissue. DUXAP10 expression is higher in samples taken from primary ATC sites (cBioPortal) and its overexpression is correlated with distant metastasis and lower patient survival (cBioPortal, GEPIA). Our data supports DUXAP10 overexpression in ATC cell line T238, and the transcriptional reduction of its expression was achieved using CRISPRi technology. Supporting experiments show a significant role for DUXAP10 at the interface of metastatic phenotypes driven by the convergence of the Unfolded Protein Response (UPR) and Wnt/β-catenin-induced epithelial-to-mesenchymal transition (EMT). Hypoxia is a central issue at ATC tumor sites, resulting in an unremitting survival adaptation that by-passes ER-stress induced apoptotic branches of the UPR. Our data showed that ER-stress induced upregulation of EMT phenotypes was ameliorated by CRISPRi-reduced DUXAP10 expression- functioning via β-catenin-driven rapid growth induction of PERK-mediated EMT. DUXAP10 was determined to have strong nuclear localization in T238. Current work includes investigation of its protein-scaffolding role in the nucleus, and how this specific function is impacting mediators of the UPR and Wnt/β-catenin regulation. Other supporting data confirms a role for DUXAP10 in T238 proliferation, clonogenicity, apoptosis, cell-cycle regulation, invasion, migration and rate of RNA synthesis. These data reveal the novelty of DUXAP10, and that its over-expression may increase the negative consequences of ATC metastasis. Citation Format: Nicole R. DeSouza, Kate Nielsen, Danielle Quaranto, Michelle Carnazza, Tara Jarboe, Kaci Kopec, Robert Suriano, David Garber, Steven Hemmerdinger, Augustine Moscatello, Humayun K. Islam, Raj K. Tiwari, Jan Geliebter. Long non-coding RNA DUXAP10 regulates mediators of endoplasmic reticulum stress-induced epithelial-to-mesenchymal transition in anaplastic thyroid 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 2798.