Pregranulosa cells upregulate cardiac troponin I Tnni3 upon cell cycle resumption during primordial follicle activation.

Frost, Emily R; Taylor, Güneş; Boeing, Stefan; Galichet, Christophe; Baker, Mark A.; Sutherland, Jessie M.; Lovell-Badge, Robin

doi:10.1101/2022.10.24.513438

Cited by 1 publication

(1 citation statement)

References 90 publications

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“…While no differences were observed in terms of ERK1/2 proteins, phosphorylation of AKT, GSK3β, and Smad2/3 phosphorylation was significantly reduced in CRISPR clones (Figure 3a). Interestingly, this phenomenon was accompanied by a significant increase of p27 (Figure 3b), a FOXL2 regulated player [39,40] involved in cell cycle inhibition whose expression is known to be also negatively controlled by PI3K pathway [41].…”

Section: Resultsmentioning

confidence: 99%

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

Amarilla-Quintana,

Navarro,

Ramos

et al. 2024

Preprint

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FOXL2 is a transcription factor essential for sex determination and ovary development and maintenance. Mutations in this gene are implicated in syndromes involving premature ovarian failure and granulosa cell tumors (GCTs). This rare cancer accounts for less than 5% of diagnosed ovarian cancers and is causally associated with the FOXL2 c.402C>G, p.C134W mutation in 97% of the adult cases (AGCTs). In this study, we employed CRISPR technology to specifically eliminate the FOXL2 c.402C>G mutation in granulosa tumor cells. Our results show that this Cas9-mediated strategy selectively targets the mutation without affecting the wild-type allele. Granulosa cells lacking the FOXL2 c.402C>G exhibit a reduced malignant phenotype, with significant changes in cell proliferation, invasion, and cell death. Furthermore, these modified cells are more susceptible to Dasatinib and Ketoconazole. Transcriptomic and proteomic analyses reveal that CRISPR-modified granulosa tumor cells shift their expression profiles towards a wild-type like phenotype. Additionally, this altered expression signature has led to the identification of new compounds with antiproliferative and pro-apoptotic effects on granulosa tumor cells. Our findings demonstrate the potential of CRISPR technology for the specific targeting and elimination of a mutation causing granulosa cell tumors, highlighting its therapeutic promise for treating this rare ovarian cancer.Simple SummaryAdult granulosa cell tumors (AGCTs), characterized by a specific point mutation (C134W) in the gene FOXL2, are less than 5% of all the diagnosed ovarian cancers. Surgery is the cornerstone treatment for AGCT even at relapse, with systemic therapy showing poor results. The aim of our study is to explore the potential therapeutic effect of the elimination of the C134W mutation. To achieve our goal, we have eliminated the mutant allele using CRISPR technology. Our results demonstrate that CRISPR-mediated elimination of FOXL2-C134W reduces the malignant phenotype of granulosa tumor cells, which change their transcriptional, proteomic, and cellular phenotype to a wild type like, granulosa type. Moreover, the induced changes allowed us to find new compounds with antitumoral activity. This work highlights the therapeutic potential of CRISPR mediated technology for the treatment of AGCT.

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Section: Resultsmentioning

confidence: 99%