Proceedings of the National Academy of Sciences of the United States of America · 2026
Differential Wnt/β-catenin signaling via TCF7L2/LEF1 binding specificity shapes cellular and tumor phenotypes.
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Kluiver Thomas A, Nordin Anna, Lu Yuyan, Guo Xuan, Schubert Stephanie A, Yeung Darien, Ardisasmita Arif Ibrahim, Terpstra Wessel, Zhang Chang, Duan Xiaochen, Savur Rishi, van den Heuvel Marius C, de Meijer Vincent E, de Kleine Ruben H, Kraal Kathelijne, de Krijger Ronald R, Zsiros József, Cantù Claudio, Peng Weng Chuan
Аннотация
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.