Condensate-driven transcriptional reprogramming to define core vulnerabilities in esophageal and gastric cancers.

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e15119 Background: Biomolecular condensates organize key nuclear functions through phase separation, yet their roles in gastrointestinal tumorigenesis remain poorly defined. Integrating multi-omics profiling, functional genomics, and biophysical modeling, we reveal that esophageal and gastric cancers share a condensate-enriched transcriptional architecture driven by intrinsically disordered regulators of transcription, RNA processing, and replication stress. Methods: RNA-seq data from GTEx and TCGA were normalized and analyzed for differential expression in esophageal and gastric cancers. Condensate-related genes were defined using GO terms and assessed with DepMap dependency data. To identify those proteins able to form biomolecular condensates on their own, we employed a machine-learning predictor (1), high-resolution coarse-grained molecular dynamics simulations (2) and experimental in vitro characterization of single-protein condensates via turbidity at 340 nm. Results: Transcriptomic analyses identified a hyperactive transcriptional state with upregulation of condensate-associated genes, including TOPBP1 and CHERP. Dependency mapping demonstrated that these scaffolds are essential for tumor cell viability, defining a conserved condensate core across tumor types. Machine-learned predictions and coarse-grained molecular dynamics confirmed their high intrinsic disorder and low saturation concentration to undergo phase-separation, consistent with autonomous condensate formation and with our in vitro estimation of the saturation concentration of CHERP. Furthermore, expression profiling showed that TOPBP1 and CHERP are activated during tumorigenesis and downregulated in metastasis, reflecting adaptive remodeling of nuclear condensates during disease progression. Conclusions: Together, these findings establish condensate organization as a fundamental mesoscale principle in upper gastrointestinal cancers and nominate condensate scaffolds as tractable therapeutic vulnerabilities. References: R Tejedor A, Aguirre Gonzalez A, Maristany MJ, Chew PY, Russell K, Ramirez J, Espinosa JR, Collepardo-Guevara R. Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates. ACS Cent Sci. 2025 Feb 11;11(2):302-321. doi: 10.1021/acscentsci.4c01617. PMID: 40028356; PMCID: PMC11869137. Von Bülow S, Tesei G, Zaidi FK, Mittag T, Lindorff-Larsen K. Prediction of phase-separation propensities of disordered proteins from sequence. Proc Natl Acad Sci U S A. 2025 Apr;122(13):e2417920122. doi: 10.1073/pnas.2417920122. Epub 2025 Mar 25. PMID: 40131954; PMCID: PMC12002312.

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