Metabolic characteristics of granulosa cell tumor: role of PPARγ signaling†

Abstract

Granulosa cell tumors are relatively rare, posing challenges for comprehension and therapeutic development due to limited cases and preclinical models. Metabolic reprogramming, a hallmark of cancer, manifests in granulosa cell tumors with notable lipid accumulation and increased expression of peroxisome proliferator-activated receptor gamma (PPARγ), a key lipid metabolism regulator. The roles of these features, however, remain unclear. In our previous work, we established a granulosa cell tumor model in mice by introducing a constitutively active Pik3ca mutant in oocytes, enabling the study of predictable tumor patterns from postnatal day 50. In this study, we characterized metabolic alterations during tumorigenesis (postnatal day 8 to day 50) and tumor growth (day 50 to day 65) in this model and explored the impact of PPARγ antagonism on human granulosa cell tumor proliferation. The tumor exhibited significant lipid accumulation, with PPARγ and the proliferation marker Ki67 co-localizing at postnatal day 65. Transcriptome analysis demonstrates that pathways for lipid metabolism and mitochondrial oxidation are promoted during tumorigenesis and tumor growth, respectively. Overlappingly upregulated genes during tumorigenesis and tumor growth are associated with lipid metabolism pathways. Correspondingly, mouse granulosa cell tumor shows overexpression of peroxisome proliferator-activated receptor gamma and DGAT2 proteins at postnatal day 65. Furthermore, GW9662 reduces the proliferation of KGN human granulosa cell tumor cells and decreases the phosphorylation of AKT and SMAD3. Our findings identify metabolic abnormalities in ooPIK3CA* granulosa cell tumor model and suggest peroxisome proliferator-activated receptor gamma as a potential driver for primary granulosa cell tumor growth.

Keywords: granulosa cell tumor; oocyte-specific Pik3ca* knock-in; peroxisome proliferator–activated receptor gamma.