2026-05-20T04:15:53Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260002025-12-18T12:59:56Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616col_20.500.12105_19617col_20.500.12105_25179

00925njm 22002777a 4500 dc Amarilla-Quintana, Sandra author Navarro, Paloma author Hernández Martínez, Iván author Ramos, Alejandra author Montero-Calle, Ana Maria author Cabezas-Sainz, Pablo author Barrero, Maria author Megias Vazquez, Diego author Vilaplana-Marti, Borja author Epifano, Carolina author Gomez-Dominguez, Deborah author Monzon-Fernandez, Sara author Cuesta de la Plaza, Isabel author Sánchez, Laura author Barderas Manchado, Rodrigo author Garcia-Donas, Jesus author Martin, Alberto author Perez de Castro, Ignacio author 2025-01-08 Forkhead box L2 (FOXL2) encodes 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 FOXL2 c.402C>G exhibit a reduced malignant phenotype, with significant changes in cell proliferation and invasion. 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 GCTs, highlighting its therapeutic promise for treating this rare ovarian cancer. Amarilla-Quintana S, Navarro P, Hernández I, Ramos A, Montero-Calle A, Cabezas-Sainz P, Barrero MJ, Megías D, Vilaplana-Martí B, Epifano C, Gómez-Dominguez D, Monzón S, Cuesta I, Sánchez L, Barderas R, García-Donas J, Martín A, Pérez de Castro I. CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds. Mol Oncol. 2025 Jan 8. 10.1002/1878-0261.13799 1878-0261 1574-7891 Molecular Oncology 39776254 https://hdl.handle.net/20.500.12105/26000 CRISPR FOXL2 Granulosa cell tumor Rare cancer CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds