Temporal dynamics of Wnt-dependent transcriptome reveal an oncogenic Wnt/MYC/ribosome axis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Signaling

Background:

• Activating mutations in the Wnt pathway are crucial drivers for numerous cancers.
• The precise downstream targets and signaling cascades activated by Wnt ligands remain incompletely elucidated.
• Wnt-addicted cancers represent a significant clinical challenge due to incomplete understanding of their molecular underpinnings.

Purpose of the Study:

• To comprehensively map Wnt-dependent signaling pathways in Wnt-addicted pancreatic cancer.
• To investigate the temporal dynamics of Wnt-activated gene expression and protein regulation.
• To identify key molecular mechanisms by which Wnt signaling drives cancer proliferation.

Main Methods:

• Utilized a porcupine (PORCN) inhibitor in an orthotopic model of Wnt-addicted pancreatic cancer.
• Performed a comprehensive time-course transcriptomic analysis following drug perturbation.
• Validated findings in additional Wnt-addicted cancer models.

Main Results:

• Discovered that Wnt signaling directly and indirectly regulates over 3,500 genes (23% of the transcriptome).
• Identified dual regulation through Wnt/β-catenin and modulation of transcription factor protein levels via Wnt-dependent stabilization of proteins (Wnt/STOP).
• Demonstrated that Wnt/β-catenin and Wnt/STOP signaling centrally control ribosome biogenesis.

Conclusions:

• Wnt/β-catenin and Wnt/STOP are critical regulators of ribosome biogenesis in Wnt-addicted cancers.
• Ribosome biogenesis is a key driver of cancer cell proliferation regulated by Wnt signaling.
• This research elucidates novel Wnt pathway targets and mechanisms relevant to cancer therapy.