Differential Wnt/β-catenin signaling via TCF7L2/LEF1 binding specificity shapes cellular and tumor phenotypes
- Thomas A. Kluiver
- Anna Nordin
- Yuyan Lu
- Xuan Guo
- Stephanie A. Schubert
- Darien Yeung
- Arif Ibrahim Ardisasmita
- Wessel Terpstra
- Chang Zhang
- Xiaochen Duan
- Rishi Savur
- Marius C. van den Heuvel
- Vincent E. de Meijer
- Ruben H. de Kleine
- Kathelijne Kraal
- Ronald R. de Krijger
- József Zsiros
- Claudio Cantù
- Weng Chuan Peng
2026-06-10
The mechanisms by which Wnt/β-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 (β-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 β-catenin engages distinct genomic regions, dictated by differential association with TCF/LEF family transcription factors. Specifically, we define a sequence-specific regulatory element engaged by β-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 β-catenin-TCF/LEF interaction orchestrates context-specific Wnt signaling outcomes.