Unveiling the impact of AKT1 pathogenic variants in Juvenile Granulosa Cell Tumors Using a Drosophila model

ABSTRACT: Juvenile-type granulosa cell tumors (JGCTs) manifest during the prepubertal period as precocious pseudo-puberty and/or dysmenorrhea. We have previously identified pathogenic variants in AKT1 in JGCTs. The current study aims to understand how these variants affect cellular function at the phenotypic and molecular levels. To do this, we created transgenic Drosophila models expressing wild-type (WT) AKT1 and four pathogenic variants, under the control of tissue-specific promoters. Drosophila wings were used to assess the effects of mutated AKT1 on cell division and growth by measuring trichome density. Wings expressing mutated AKT1 showed an increased surface area and a reduced trichome density, indicating the presence of probably larger cells. In ovarian follicular cells, the AKT1 WT localized mainly in the cytoplasm, while the mutated variants are found in the plasma membrane. This localization led to various morphological abnormalities and a significant increase in cell size. Mass spectrometry (MS) revealed a number of differentially expressed proteins (DEPs) and phospho-peptides pointing to significant changes in pathways such as glycolysis and Rho GTPases signaling in response to AKT1 mutation. At the transcriptional level, as expected for activating oncogenic mutations, we found a clear gain-of-function of the mutated forms for a gene subset. However, we also found that a series of genes up-regulated by WT AKT1 were less well activated by the mutated forms. This suggests the existence of a potential loss-of-function of mutated AKT1 on the transcriptional regulation of this specific gene subset, pointing to an unanticipated mechanistic complexity. The analysis of the network of interactions involving DEPs, differentially phosphorylated proteins and transcription factors, probably mediating the aforementioned transcriptional alterations, highlights the central role of AKT1 as a cancer driver. Our results taken altogether underscore the utility of Drosophila as a model to understanding the biological relevance of AKT mutations in cancer.

INSTRUMENT(S):

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

TISSUE(S): Oocyte

SUBMITTER: Guillaume CHEVREUX  

LAB HEAD: Anne-Laure, Todeschini

PROVIDER: PXD060549 | Pride | 2026-01-12

REPOSITORIES: Pride