Condensate-Driven Transcriptional Reprogramming Defines Core Vulnerabilities in Esophageal and Gastric Cancers

Abstract Biomolecular condensates organize key nuclear functions by compartmentalizing biomolecules, yet their contribution to gastrointestinal tumorigenesis remains poorly defined. Integrating multi-omics profiling, functional genomics, and molecular dynamics simulations, we reveal that esophageal and gastric cancers share a condensate-enriched transcriptional program driven by intrinsically disordered proteins involved in transcription, RNA processing, and replication stress. Transcriptomic analyses identify a hyperactive transcriptional state with upregulation of condensate-associated genes, including TOPBP1 and CHERP . Dependency mapping demonstrates that these proteins are essential for tumor cell viability, defining a conserved condensate core across different tumor types. Machine-learned predictions and residue-resolution coarse-grained simulations confirm that TOPBP1 and CHERP undergo phase separation through homotypic interactions mediated by intrinsically disordered regions, with saturation concentrations below 2 µM, consistent with spontaneous condensate formation observed in vitro. Together, these findings establish condensate organization as a fundamental mesoscale principle in upper gastrointestinal cancers and nominate condensate scaffolds as tractable therapeutic vulnerabilities.