An inducible FOXL2-dependent mouse model of ovarian adult type granulosa cell tumor

Gynecol Oncol. 2025 Mar:194:125-130. doi: 10.1016/j.ygyno.2025.01.011.

Abstract

Background: Adult-type granulosa cell tumors (AGCTs) are rare ovarian sex cord/stromal tumors with near-universal hotspot mutations in FOXL2 (c.C402G; p.Cys134Trp). Progress in the treatment of relapsed AGCT has been hindered by the lack of high-fidelity FOXL2-based mouse models. To address this critical unmet need, we created and validated a genetically engineered inducible mouse model of the human FOXL2 mutation that recapitulates the key features of the human disease.

Methods: Gene targeting in embryonic stem cells was used to introduce a Cre-inducible Foxl2C130W allele (mouse equivalent of the human oncogenic mutation) into the endogenous mouse Foxl2 locus. Animals with the Foxl2C130W-FLEx allele were crossed with those carrying a well characterized Amhr2-Cre allele to achieve perinatal recombination in granulosa cells. Small animal magnetic resonance imaging (MRI) was used to monitor for tumor growth. Ovarian tumors were characterized using immunohistochemistry interpreted by veterinary and clinical gynecologic oncology pathologists.

Results: Female Amhr2-Cre; Foxl2+/C130W-FLEx animals developed normally into adulthood. By 10 months of age, all eight Amhr2-Cre; Foxl2+/C130W-FLEx females that were imaged by MRI exhibited cystic uterine changes. By 12-14 months of age, three Amhr2-Cre; Foxl2+/C130W-FLEx females developed unilateral granulosa cell tumors ranging from microscopic to grossly visible size. The morphology and immunophenotype were consistent with human AGCT, as FOXL2, SF1 and Inhibin alpha were positive in all tumor cells.

Conclusions: A Amhr2-Cre; Foxl2+/C130W-FLEx mouse model recapitulates key aspects of the human AGCT including a dependence upon the causative FOXL2 mutation, concomitant uterine hyperplasia, and an age-dependent onset of tumors at the time of decreasing ovarian function. This new resource will accelerate translational research and therapeutic discovery for relapsed AGCT.

Keywords: Granulosa cell tumor; Mouse model; Translational science.

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Female
  • Forkhead Box Protein L2* / genetics
  • Granulosa Cell Tumor* / diagnostic imaging
  • Granulosa Cell Tumor* / genetics
  • Granulosa Cell Tumor* / metabolism
  • Granulosa Cell Tumor* / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Transgenic
  • Mutation
  • Ovarian Neoplasms* / diagnostic imaging
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / metabolism
  • Ovarian Neoplasms* / pathology

Substances

  • Forkhead Box Protein L2
  • Foxl2 protein, mouse
  • FOXL2 protein, human

Supplementary concepts

  • Granulosa cell tumor of the ovary