Authors
Kluiver, T. A., Nordin, A., Lu, Y., Zhang, C., Schubert, S. A., Duan, X., Savur, R., van den Heuvel, M. C., de Meijer, V. E., de Kleine, R. H., Kraal, K., de Krijger, R. R., Zsiros, J., Cantu, C., Peng, W. C.
Abstract
The mechanisms by which Wnt/{beta}-catenin signaling regulates gene expression in a tissue- and context-specific manner remain poorly understood, limiting our ability to target the aberrant cell growth typical of many Wnt-driven cancers. Here we focus on malignant liver tumors driven by activating CTNNB1 ({beta}-catenin) mutations that nevertheless display distinct phenotypic states and Wnt outputs. By profiling patient-derived organoids via single-cell transcriptomics and chromatin dynamics, we identify subtype-specific transcriptional and epigenetic profiles. Using CUT&RUN, we show that {beta}-catenin engages distinct genomic regions, dictated by differential association with TCF/LEF family transcription factors. Specifically, we define a novel sequence-specific regulatory element engaged by {beta}-catenin only upon interaction with TCF7L2, revealing that partner choice, independent of CTNNB1 mutational status, ultimately determines cell fate. Our findings, validated across multiple tumor models and patient tissues, offer a framework for understanding how differential {beta}-catenin-TCF/LEF interaction orchestrates context-specific Wnt signaling outcomes.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 06 Nov 2025.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 75
- Comments 0