Fukunaga, Y. | bioRxiv Science

bioRxiv2026

Epigenetic Control of Spatiotemporal Dynamics of Pancreatic Cancer Cells via Brg1-Rac1 Signaling

Pancreatic ductal adenocarcinoma (PDA) arises from distinct precursor lesions with different clinical outcomes, yet the mechanisms linking epigenetic regulation to invasive cell behavior remain poorly understood. Here, we investigate how the chromatin remodeler Brg1 influences the dynamic properties of cancer cell migration. Using a biomimetic supported membrane system combined with label-free interferometric imaging, we quantitatively analyze the spatiotemporal dynamics of PDA cells derived from pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMN). Despite their similar morphology under conventional conditions, PanIN- and IPMN-derived PDA cells exhibit markedly different migration behaviors. PanIN-derived cells migrate faster and display enhanced dynamic remodeling, whereas IPMN-derived cells show persistent elongation with limited displacement. These differences are captured by quantitative analyses of cell trajectories and deformation dynamics. Mechanistically, PanIN-derived PDA cells exhibit elevated Rac1 activity, supporting a model in which a Brg1-Rac1 axis regulates cytoskeletal dynamics and migration behavior. Together, our findings demonstrate that epigenetic regulation is linked to distinct dynamic phenotypes of cancer cells and highlight the importance of quantitative analysis of cell behavior for understanding invasive potential.

biophysics↗

bioRxiv2026

Multiple-Context Training Enhances Generalization of Cued Fear Extinction and Requires the Dorsal Hippocampus

BACKGROUNDMultiple-session fear extinction (FE) models exposure therapy, which also occurs over many sessions. In humans, conducting extinction training across multiple contexts improves fear suppression as compared to a single context, but rodent work delineating boundary conditions and neural mechanisms remains sparse. METHODSWe compared single-context FE (SCFE) versus multiple-context FE (MCFE) in 129S1 and C57BL/6J mice, manipulating context familiarity (familiar vs novel FE contexts). Outcomes included FE acquisition and tests for fear relapse such as recent (2 d) and remote (30 d) recall in trained, extinction, and novel contexts, as well as reinstatement tests. We mapped extinction-related neural activity with dual Fos labeling (TRAPxFos immunofluorescence) and graph analyses of regional co-activation, and used chemogenetic inhibition to selectively silence dorsal (dHP) or ventral hippocampus (vHP) during extinction. RESULTSMCFE produced greater across-session reduction in freezing than SCFE. The MCFE advantage did not require contextual novelty. MCFE also enhanced short- (2 d) and long-term (30 d) recall in a novel context, but did not prevent recovery over time or US-induced reinstatement. Dual-labeling revealed that MCFE strengthened hippocampal-prefrontal co-activation (with relatively weaker prefrontal-amygdala coupling than SCFE). Chemogenetic silencing of dHP, but not vHP, selectively impaired between-session extinction under MCFE and abolished the MCFE benefit; hippocampal silencing did not improve SCFE. CONCLUSIONSConducting extinction across multiple contexts enhances acquisition and recall relative to SCFE, without requiring novelty, and engages distinct hippocampal-prefrontal circuit dynamics. dHP activity is necessary for the MCFE-specific improvement, highlighting a circuit mechanism in which distributing extinction across contexts augments fear reduction.

neuroscience↗