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Differential Wnt/β-catenin signaling via TCF7L2/LEF1 binding specificity shapes cellular and tumor phenotypes

Thomas A Kluiver1, Anna Nordin2,3,4, Yuyan Lu1,5

  • 1Princess Máxima Center for Pediatric Oncology, Utrecht 3584 CH, The Netherlands.

Proceedings of the National Academy of Sciences of the United States of America
|June 10, 2026
PubMed

Insights

Wnt/β-catenin signaling in liver cancer is context-specific. β-catenin partners with different TCF/LEF factors, like TCF7L2, to control gene expression and cell fate, regardless of mutation status.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Epigenetics

Background:

  • Wnt/β-catenin signaling is crucial for development and implicated in various cancers.
  • Aberrant signaling, particularly activating CTNNB1 mutations, drives liver tumorigenesis.
  • Understanding context-specific signaling is vital for targeted cancer therapies.

Purpose of the Study:

  • To elucidate the mechanisms of tissue- and context-specific Wnt/β-catenin signaling in liver cancer.
  • To identify subtype-specific transcriptional and epigenetic profiles in patient-derived tumors.
  • To determine how differential β-catenin-TCF/LEF interactions influence cell fate.

Main Methods:

  • Single-cell transcriptomics and chromatin dynamics profiling of patient-derived organoids.
  • CUT&RUN assays to map β-catenin genomic engagement.
  • Validation across multiple tumor models and patient tissues.

Main Results:

  • Identified distinct transcriptional and epigenetic profiles in different liver tumor subtypes.
  • β-catenin associates with specific genomic regions, influenced by TCF/LEF transcription factors.
  • Defined a TCF7L2-dependent regulatory element engaged by β-catenin, dictating cell fate.

Conclusions:

  • Partner choice in β-catenin-TCF/LEF interactions, not just mutation status, determines Wnt signaling outcomes.
  • Provides a framework for understanding context-specific Wnt signaling in cancer.
  • Offers potential therapeutic strategies targeting specific Wnt pathway interactions in liver cancer.
Keywords:
TCF/LEFWnt signalingcancernovel motifβ-catenin

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