STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Aberrant Wnt pathway signaling drives cancer progression.
• RNF43 loss-of-function mutations are common in aggressive cancers lacking targeted therapies.
• Identifying novel regulators and therapeutic targets in the Wnt pathway is crucial.

Purpose of the Study:

• To identify novel regulators of Wnt signaling, particularly in the context of RNF43 loss.
• To investigate the role of STT3A in Wnt pathway activation and cancer growth.
• To explore STT3A as a potential therapeutic target for RNF43-deficient cancers.

Main Methods:

• Utilized a double death trap (DDT) Wnt reporter system.
• Performed a genome-wide CRISPR screen to identify essential regulators.
• Employed genetic and pharmacological inhibition of STT3A.
• Assessed tumor growth in cell lines, organoids, and spontaneous tumors.
• Investigated the mechanism of STT3A action on Wnt/β-catenin signaling and LRP6 glycosylation.

Main Results:

• Identified STT3A as an essential regulator of Wnt signaling.
• Demonstrated that STT3A inhibition suppresses aberrant Wnt activity caused by RNF43/ZNRF3 loss.
• Showed that STT3A suppression blocks the growth of RNF43-deficient cancers in vitro and in vivo.
• Elucidated that STT3A regulates Wnt/β-catenin signaling via LRP6 glycosylation, which is critical for Wnt ligand binding.
• Observed milder effects of STT3A depletion on bone homeostasis.

Conclusions:

• Established STT3A as a critical regulator of Wnt signaling through LRP6 glycosylation.
• Validated STT3A as a promising therapeutic target for RNF43-deficient cancers.
• Highlighted the potential of targeting STT3A to overcome resistance in aggressive cancers lacking targeted therapies.