Differential Wnt/β-catenin signaling via TCF7L2/LEF1 binding specificity shapes cellular and tumor phenotypes
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (19)
Thomas A. Kluiver
Princess Máxima Center for Pediatric Oncology
Anna Nordin
Wallenberg Centre for Molecular Medicine, Linköping University
Yuyan Lu
Princess Máxima Center for Pediatric Oncology
Xuan Guo
Princess Máxima Center for Pediatric Oncology
Stephanie A. Schubert
Princess Máxima Center for Pediatric Oncology
Darien Yeung
Princess Máxima Center for Pediatric Oncology
Arif Ibrahim Ardisasmita
Princess Máxima Center for Pediatric Oncology
Wessel Terpstra
Princess Máxima Center for Pediatric Oncology
Chang Zhang
Xiaochen Duan
Princess Máxima Center for Pediatric Oncology
Rishi Savur
Princess Máxima Center for Pediatric Oncology
Marius C. van den Heuvel
Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen
Vincent E. de Meijer
Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen
Ruben H. de Kleine
Department of Surgery, Section of Hepatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen
Kathelijne Kraal
Princess Máxima Center for Pediatric Oncology
Ronald R. de Krijger
Princess Máxima Center for Pediatric Oncology
József Zsiros
Princess Máxima Center for Pediatric Oncology
Claudio Cantù
Wallenberg Centre for Molecular Medicine, Linköping University
Weng Chuan Peng
Princess Máxima Center for Pediatric Oncology