Key result
In a mouse model, PPARγ and lipid metabolism pathways were upregulated, and PPARγ antagonism with GW9662 reduced the proliferation of human KGN granulosa cell tumor cells.
Why the study?
Granulosa cell tumors exhibit lipid accumulation and increased PPARγ expression, but the roles of these metabolic features remain unclear.
Does PPARγ antagonism reduce proliferation in granulosa cell tumor models?
Does PPARγ antagonism reduce proliferation in granulosa cell tumor models?
PPARγ antagonism reduces proliferation in granulosa cell tumor models, suggesting PPARγ as a potential driver for tumor growth.
PPARγ antagonism merits exploration as a target in granulosa cell tumors; leaves open translation from cell models to patients.
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.
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Yu et al. (2023) studied Granulosa cell tumor. PPARγ antagonism (GW9662) was evaluated on Tumorigenesis, tumor growth, and cell proliferation. In a mouse model, PPARγ and lipid metabolism pathways were upregulated, and PPARγ antagonism with GW9662 reduced the proliferation of human KGN granulosa cell tumor cells.
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