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

Ileana C. Cuevas, Subhransu S. Sahoo, Ashwani Kumar, He Zhang, Jill Westcott, Mitzi Aguilar, Jeremy D. Cortez, Stephanie A. Sullivan, Chao Xing, D. Neil Hayes, Rolf A. Brekken, Victoria L. Bae-Jump, Diego H. Castrillon

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)25880-25890
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number51
DOIs
StatePublished - Dec 17 2019

Keywords

  • Epithelial-mesenchymal transition
  • Fbxw7
  • Pten
  • Tp53
  • Uterine carcinosarcoma

ASJC Scopus subject areas

  • General

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  • Cite this

    Cuevas, I. C., Sahoo, S. S., Kumar, A., Zhang, H., Westcott, J., Aguilar, M., Cortez, J. D., Sullivan, S. A., Xing, C., Neil Hayes, D., Brekken, R. A., Bae-Jump, V. L., & Castrillon, D. H. (2019). Fbxw7 is a driver of uterine carcinosarcoma by promoting epithelial-mesenchymal transition. Proceedings of the National Academy of Sciences of the United States of America, 116(51), 25880-25890. https://doi.org/10.1073/pnas.1911310116