Abstract A053: Steroid receptors modulate oncogenic signaling and drive cell migration in pancreatic ductal adenocarcinoma

Steroid hormone receptors (SRs) drive progression of hormone-dependent cancers (e.g. breast and prostate) where they are targeted by lifesaving treatments designed to block SR actions. In pancreatic ductal adenocarcinoma (PDA), glucocorticoid receptor (GR) and progesterone receptor (PR) are mediators of tumor progression, micropinocytosis, and immune evasion. Furthermore, PDA is associated with increased expression of both GR and PR. PDA is a particularly lethal disease with a 5-year survival around 11%, frequently late-stage diagnosis, and poor treatment options. Despite this, SR mechanisms in PDA remain unexplored. We hypothesize that SRs (namely GR and PR) contribute to PDA progression, and that ligand-binding, post-translational modifications, and selected coregulators modulate SR actions in the context of stress-activated signaling pathways associated with aggressive PDA phenotypes. Here, we present a study of SRs in PDA cell culture with a focus on SR expression, oncogenic signaling, and SR-mediated advanced cancer phenotypes. Herein, we characterized cellular migration via transwell migration assay, mRNA expression via qPCR, and protein expression via western blot. We first defined variable SR expression levels in a panel of human immortalized PDA cell models (Aspc-1, Bxpc-3, Capan-1, CFPAC, HPAF-II, Hs 766T, MIA Paca-2, Panc-1, Panc 10.05). We next performed studies focused on SR phosphorylation in response to steroids and cytokines as well as interplay between SRs and signaling pathways including p38 MAP Kinase (MAPK), AKT, and RAS pathways. Finally, we measured cell migration in response to treatment with SR ligands, SR inhibitors, and cytokines, including TGFbeta, IL-1beta, and Leukemia Inhibitory Factory, all of which are prevalent in the PDA tumor microenvironment and known to promote PDA progression. We observed that glucocorticoid or cytokine treatments induced increased migration of Panc-1, MIA Paca-2, CFPAC, and Panc 10.05 cells relative to vehicle-treated controls. Treatment with SR antagonists (mifepristone, relacorilant) attenuated cytokine- and serum-induced migration. In response to either ligand or cytokine treatment, PDA cell lines exhibited phosphorylation of GR at Ser134, a stress-induced p38 MAPK consensus phosphorylation site that drives advanced phenotypes in triple negative breast cancer models. Phosphorylation of GR Ser134 is mediated by components from oncogenic signaling cascades such as p38 MAPK and AKT. Finally, we have determined that GR and KRAS interact via coimmunoprecipitation in PDAC cell line CFPAC. This study provides preliminary analyses of SR expression in PDA models and SR integration stress-activated signaling pathways linked to aggressive PDA biology. Future studies will include invasion and sphere-forming assays, rigorous interrogation of stress-activated signaling pathways, SR-KRAS and SR-SR interactions, and transcriptional studies that define SR-dependent gene signatures in PDA. Our long term goal is to elucidate novel paths to improved PDA screening and treatment. Citation Format: Oliver M. Stockert, Carol A. Lange. Steroid receptors modulate oncogenic signaling and drive cell migration in pancreatic ductal adenocarcinoma [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): nr A053.