CD73 restrains mutant β-catenin oncogenic activity in endometrial carcinomas

TL;DR

CD73 limits the cancer-causing effects of mutant β-catenin in endometrial carcinomas, and its loss is linked to cancer recurrence.

Contribution

CD73 is identified as a novel regulator of mutant β-catenin oncogenic activity in endometrial carcinomas.

Findings

CD73 loss increases β-catenin–TCF/LEF transcriptional activity and promotes recurrence.

CD73 sequesters mutant β-catenin to the membrane, limiting its oncogenic activity.

CD73 loss is linked to Wnt–TCF/LEF–dependent gene expression programs associated with cancer stemness.

Abstract

Approximately 30% of patients with endometrial carcinomas (ECs) with exon 3 CTNNB1 (β-catenin) mutations experience disease recurrence, whereas others with the same mutations remain recurrence-free. The molecular factors driving mutant β-catenin’s oncogenic and clinical variability are unknown. Here we show that CD73 restrains the oncogenic activity of exon 3 β-catenin mutants, and CD73 loss is associated with recurrence. Using 7 patient-specific β-catenin mutants, together with genetic deletion or ectopic expression of CD73, we demonstrate that CD73 loss increases β-catenin–TCF/LEF transcriptional activity. In CD73-deficient cells, membrane levels of mutant β-catenin decreased, which corresponded with increased levels of nuclear and chromatin-bound mutant β-catenin. These results suggest that CD73 sequesters mutant β-catenin to the membrane to limit its oncogenic activity. Adenosine A1 receptor deletion phenocopied the effects of CD73 loss, implicating adenosine receptor signaling in this regulation. Ectopic CD73 expression suppressed the invasiveness and stemness capacity of β-catenin–mutant EC cells. TCGA analyses, GeoMx digital spatial profiling, and functional analyses showed that CD73 loss drives distinct Wnt–TCF/LEF–dependent gene expression programs linked to cancer cell stemness. These findings identify CD73 as a key regulator of mutant β-catenin, providing mechanistic insight into the variability of recurrence in CTNNB1-mutant EC.

CD73 regulates the oncogenic activity of mutant b-catenin. This finding may help improve predicting which endometrial cancer patients are at a higher risk of recurrence.

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