Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition

Significance Uterine carcinosarcoma (UCS) is an aggressive endometrial cancer variant distinguished from endometrial adenocarcinoma (EC) by admixed malignant epithelial and mesenchymal components (carcinoma and sarcoma). The molecular events underlying UCS are enigmatic, as cancer gene mutations are generally shared among UCS/EC. We take advantage of genetic approaches in mice to show that inactivation of Fbxw7 and Pten results in UCS through spontaneous acquisition of mutations in a third gene (Tp53), arguing for strong biological selection and synergism in UCS. We used this UCS model including tumor-derived cell lines to show that Fbxw7 loss drives epithelial–mesenchymal transition, explaining Fbxw7’s role in UCS. This model system argues that simultaneous genetic defects in 3 distinct pathways (Fbxw7, Pten/PI3K, Tp53) converge in UCS genesis.
Uterine carcinosarcoma is an aggressive variant of endometrial carcinoma characterized by unusual histologic features including discrete malignant epithelial and mesenchymal components (carcinoma and sarcoma). Recent studies have confirmed a monoclonal origin, and comprehensive genomic characterizations have identified mutations such as Tp53 and Pten. However, the biological origins and specific combination of driver events underpinning uterine carcinosarcoma have remained mysterious. Here, we explored the role of the tumor suppressor Fbxw7 in endometrial cancer through defined genetic model systems. Inactivation of Fbxw7 and Pten resulted in the formation of precancerous lesions (endometrioid intraepithelial neoplasia) and well-differentiated endometrioid adenocarcinomas. Surprisingly, all adenocarcinomas eventually developed into definitive uterine carcinosarcomas with carcinomatous and sarcomatous elements including heterologous differentiation, yielding a faithful genetically engineered model of this cancer type. Genomic analysis showed that most tumors spontaneously acquired Trp53 mutations, pointing to a triad of pathways (p53, PI3K, and Fbxw7) as the critical combination underpinning uterine carcinosarcoma, and to Fbxw7 as a key driver of this enigmatic endometrial cancer type. Lineage tracing provided formal genetic proof that the uterine carcinosarcoma cell of origin is an endometrial epithelial cell that subsequently undergoes a prominent epithelial–mesenchymal transition underlying the attainment of a highly invasive phenotype specifically driven by Fbxw7.