Metabolic characteristics of granulosa cell tumor: role of PPAR γ signaling

Biol Reprod. 2023 Dec 20:ioad173. doi: 10.1093/biolre/ioad173. Online ahead of print.ABSTRACTThe relative rarity of ovarian granulosa cell tumor (GCT) cases and preclinical models for GCT has posed a challenge for understanding GCT and developing therapeutics. Metabolic reprogramming is one of the key disruptions related to cancer progression. GCT exhibits significant lipid accumulation and overexpression of peroxisome proliferator-activated receptor gamma (PPARγ), a regulator of lipid metabolism. However, their roles remain unclear. Previously, we reported spontaneous GCT development in female mice with a constitutively active mutant of Pik3ca in oocytes, demonstrating predictable patterns of tumor development starting at postnatal day 50 (PD50). Thus, here, we characterized metabolic features of ooPIK3CA* GCT model during tumorigenesis (from PD8 to PD50) and tumor growth (from PD50 to PD65) and investigated the effects of PPARγ antagonism on human GCT proliferation. We found that mouse GCT exhibits significant lipid accumulation and co-localization of PPARγ and proliferation marker Ki67 at PD65. 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 GCT shows overexpression of PPARγ and DGAT2 proteins at PD65. Furthermore, G...
Source: Biology of Reproduction - Category: Reproduction Medicine Authors: Source Type: research