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

oai:repisalud.isciii.es:20.500.12105/259272025-12-18T12:56:27Zcom_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 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 Hernández Martínez, Iván 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 2024-07-03 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. Sandra Amarilla-Quintana, Paloma Navarro, Alejandra Ramos, Ana Montero-Calle, Pablo Cabezas-Sainz, Maria J Barrero, Diego Megías, Borja Vilaplana-Martí, Carolina Epifano, Déborah Gómez-Domínguez, Iván Hernández, Sara Monzón, Isabel Cuesta, Laura Sánchez, Rodrigo Barderas, Jesús García-Donas, Alberto Martín, Ignacio Pérez de Castro. bioRxiv 2024.07.01.601520; doi: https://doi.org/10.1101/2024.07.01.601520. 10.1101/2024.07.01.601520 bioRxiv https://hdl.handle.net/20.500.12105/25927 Granulosa cell tumor FOXL2 CRISPR Rare cancer CRISPR targeting of FOXL2 c.402C>G mutation reduces malignant phenotype in granulosa tumor cells and identifies anti-tumoral compounds