Recurrent COPA mutation drives R-spondin-independent Wnt activation in intestinal tumors

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Most intestinal tumors involve Wnt pathway gene mutations (e.g., APC).
• A subset of intestinal tumors lacks these canonical alterations, suggesting alternative drivers.
• The role of COPA and USP9X in intestinal tumorigenesis is largely unexplored.

Purpose of the Study:

• Identify novel genetic drivers in small intestinal tumors.
• Elucidate the mechanism by which COPA mutations promote intestinal tumorigenesis.
• Investigate the role of USP9X loss in conjunction with COPA mutations.

Main Methods:

• Analysis of small intestinal adenoma and adenocarcinoma for genetic alterations.
• Utilized patient-derived and CRISPR-engineered small intestinal organoids.
• Assessed Wnt pathway activation, LGR5 expression, and LRP6 stability.

Main Results:

• Identified recurrent in-frame deletions in COPA, often co-occurring with USP9X truncating mutations.
• COPA mutations enabled R-spondin-independent, Wnt ligand-dependent growth in organoids.
• COPA mutations stabilized LRP6, sustaining Wnt pathway activation independent of canonical drivers.
• USP9X loss potentiated the tumorigenic phenotype driven by COPA mutations.

Conclusions:

• COPA mutations represent a unique, atypical driver of intestinal tumors.
• USP9X loss acts as a cooperating lesion in COPA-driven intestinal tumorigenesis.
• This discovery reveals a novel mechanism of Wnt pathway activation in intestinal cancer.