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RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer

Maureen Spit1, Nicola Fenderico1, Ingrid Jordens1

  • 1Department of Cell Biology and Oncode Institute, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

The EMBO Journal
|September 23, 2020
PubMed

Insights

Truncating mutations in RNF43 cancer genes disrupt a suppressor role, driving tumor growth independently of Wnt signaling and reducing therapy sensitivity. This finding impacts cancer treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Stem Cell Biology

Background:

  • Wnt/β-catenin signaling is crucial for stem cell renewal and implicated in cancer development.
  • Loss of ubiquitin ligase RNF43 typically leads to Wnt hypersensitivity and susceptibility to anti-Wnt therapy.
  • Cancer mutations can alter signaling pathways in unexpected ways, necessitating detailed mechanistic studies.

Purpose of the Study:

  • To investigate the functional consequences of a specific class of RNF43 truncating mutations in cancer.
  • To elucidate the molecular mechanisms by which these mutations promote tumor growth and affect therapy response.
  • To explore the implications of these findings for understanding cancer pathogenesis and precision medicine.

Main Methods:

  • Analysis of RNF43 truncating mutations in cancer cell models.
  • Investigation of Wnt receptor endocytosis and β-catenin signaling.
  • Biochemical assays to study the interaction between RNF43, Casein kinase 1 (CK1), and β-catenin.
  • Gene editing in human colon stem cells to assess functional impacts.
  • Evaluation of sensitivity to anti-Wnt-based therapies.

Main Results:

  • Identified RNF43 truncating mutations that induce β-catenin transcription independently of Wnt receptor downregulation.
  • Demonstrated that these mutations disrupt a ubiquitin-independent suppressor function of RNF43 involving CK1 binding and phosphorylation.
  • Showed that truncated RNF43 variants trap CK1 at the plasma membrane, inhibiting β-catenin turnover.
  • Revealed that RNF43 truncations cooperate with p53 loss to promote self-renewal and proliferation in colon stem cells.
  • Observed decreased sensitivity to anti-Wnt therapy in tumors with these RNF43 variants.

Conclusions:

  • RNF43 truncating mutations represent a distinct mechanism of Wnt pathway activation in cancer.
  • These mutations confer resistance to anti-Wnt therapies by altering core signaling and cellular programs.
  • Understanding patient-derived mutations is critical for advancing precision oncology and therapeutic strategies.
Keywords:
PORCN inhibitorsRNF43Wnt signalingcancer mutationshuman colon organoids

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