Transcriptomic Profiling of Gene Expression Associated with Granulosa Cell Tumor Development in a Mouse Model

Abstract

Ovarian granulosa cell tumors (GCTs) are rare sex cord-stromal tumors, accounting for ~5% ovarian tumors. The etiology of GCTs remains poorly defined. Genetically engineered mouse models are potentially valuable for understanding the pathogenesis of GCTs. Mice harboring constitutively active TGFβ signaling (TGFBR1-CA) develop ovarian GCTs that phenocopy several hormonal and molecular characteristics of human GCTs. To determine molecular alterations in the ovary upon TGFβ signaling activation, we performed transcriptomic profiling of gene expression associated with GCT development using ovaries from 1-month-old TGFBR1-CA mice and age-matched controls. RNA-sequencing and bioinformatics analysis coupled with the validation of select target genes revealed dysregulations of multiple cellular events and signaling molecules/pathways. The differentially expressed genes are enriched not only for known GCT-related pathways and tumorigenic events but also for signaling events potentially mediated by neuroactive ligand-receptor interaction, relaxin signaling, insulin signaling, and complements in TGFBR1-CA ovaries. Additionally, a comparative analysis of our data in mice with genes dysregulated in human GCTs or granulosa cells overexpressing a mutant FOXL2, the genetic hallmark of adult GCTs, identified some common genes altered in both conditions. In summary, this study has revealed the molecular signature of ovarian GCTs in a mouse model that harbors the constitutive activation of TGFBR1. The findings may be further exploited to understand the pathogenesis of a class of poorly defined ovarian tumors.

CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds

“…Furthermore, 50% of the top-50 most up/downregulated DEGs have already been associated with granulosa cells and/or FOXL2 (Figure 5c; Supplementary Table 5). Hence, CSPG4, JPH2 and TAGLN have also been found upregulated in TGFβ -induced GCTs, when compared with wild type granulosa cells [48]. On the other hand, among the most significantly downregulated genes, CDH12 and CD55 are granulosa cell markers [49,50], whereas CYP11A1, a FOXL2 target gene [51], plays a crucial role in steroid hormone synthesis in granulosa cells [52].…”

Loss of Runx1 Induces Granulosa Cell Defects and Development of Ovarian Tumors in the Mouse

“…Finally, we compared the differentially expressed genes (DEGs) in our model with the published dataset for TGFBR1-CA ovaries, a mouse model of granulosa cell tumors caused by constitutively active TGFβ signaling [29]. There was little overlap among the genes differentially expressed in the two models (Supplementary Figure S2C).…”

Lineage tracing of mutant granulosa cells reveals in vivo protective mechanisms that prevent granulosa cell tumorigenesis

“…In addition, the utilization of genetically modified mouse models has led to the identification of several genes reportedly involved in GCT formation [ 9 – 11 ]. These genes include Inha , Smad1 , and Smad5 in the TGFβ pathway or constitutively active TGFβ signaling [ 12 – 14 ], and Foxo1 , Foxo3 , and Pten in the PI3K pathway. Interestingly, all the studied mouse models exhibited low GCT incidence in mutant females, which is consistent with the pathological characteristics of human GCTs.…”