Carcinosarcoma and Fbxw7

Carcinosarcoma is the most aggressive and least understood variant of endometrial cancer, distinguished from usual endometrial cancers by admixed malignant epithelial and mesenchymal components (carcinoma and sarcoma). We showed through genetic model systems that inactivation of Fbxw7 and Pten (with BAC-Sprr2f-Cre) always results in carcinosarcoma through an additional mutation in a 3^rd gene: Tp53. We used this model including tumor-derived cell lines to show that Fbxw7 mutation drives epithelial-mesenchymal transition, explaining Fbxw7’s role in carcinosarcoma. Lineage tracing studies of this model provided formal proof that the carcinosarcoma cell-of-origin (a long-debated question) is the endometrial epithelium. This model system demonstrates that simultaneous genetic defects in three distinct pathways (Fbxw7, Pten/PI3K, Tp53) converge in the genesis of carcinosarcoma and argue for a more central role for Fbxw7 than previously appreciated. Also, the model should prove useful for a variety of future investigations. Please see PNAS 2019 116(51):25880.