title: Dosage-dependent regulation ofVAV2expression by steroidogenic factor-1 drives adrenocortical carcinoma cell invasion.
abstract: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. Genomic studies have enabled progress in our understanding of the molecular bases of ACC, but factors that influence its prognosis are lacking. Amplification of the gene encoding the transcription factor steroidogenic factor-1 (SF-1; also known as NR5A1) is one of the genetic alterations common in ACC. We identified a transcriptional regulatory mechanism involving increased abundance of VAV2, a guanine nucleotide exchange factor for small GTPases that control the cytoskeleton, driven by increased expression of the gene encoding SF-1 in ACC. Manipulating SF-1 and VAV2 abundance in cultured ACC cells revealed that VAV2 was a critical factor for SF-1-induced cytoskeletal remodeling and invasion in culture (Matrigel) and in vivo (chicken chorioallantoic membrane) models. Analysis of ACC patient cohorts indicated that greater VAV2 abundance robustly correlated with poor prognosis in ACC patients. Because VAV2 is a druggable target, our findings suggest that blocking VAV2 may be a new therapeutic approach to inhibit metastatic progression in ACC patients.
authors.affiliation: Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France.|CNRS UMR7275, Sophia Antipolis, 06560 Valbonne, France.|NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, 06560 Valbonne, France.|Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Carmen
authors.identifier: http://orcid.org/0000-0002-9652-2502
authors.initials: C
authors.lastname: Ruggiero
authors.affiliation: Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France.|CNRS UMR7275, Sophia Antipolis, 06560 Valbonne, France.|NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, 06560 Valbonne, France.|Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Mabrouka
authors.initials: M
authors.lastname: Doghman-Bouguerra
authors.affiliation: Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Silviu
authors.initials: S
authors.lastname: Sbiera
authors.affiliation: Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Iuliu
authors.initials: I
authors.lastname: Sbiera
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London, London SE1 1UL, U.K.
authors.forename: Maddy
authors.identifier: http://orcid.org/0000-0002-2021-8379
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.
authors.forename: Bruno
authors.identifier: http://orcid.org/0000-0001-9476-4973
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.|Inserm, UMR970, Paris Cardiovascular Research Centre, 75015 Paris, France.
authors.forename: Aurélie
authors.identifier: http://orcid.org/0000-0003-2048-6805
authors.initials: A
authors.lastname: Morin
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.|Inserm, UMR970, Paris Cardiovascular Research Centre, 75015 Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Robidel
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.|Inserm, UMR970, Paris Cardiovascular Research Centre, 75015 Paris, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Favier
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|CNRS UMR8104, 75014 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, 74014 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Martin
authors.identifier: http://orcid.org/0000-0001-6170-6398
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Université Côte d'Azur, Sophia Antipolis, 06560 Valbonne, France. ninino@ipmc.cnrs.fr.|CNRS UMR7275, Sophia Antipolis, 06560 Valbonne, France.|NEOGENEX CNRS International Associated Laboratory, Sophia Antipolis, 06560 Valbonne, France.|Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Enzo
authors.identifier: http://orcid.org/0000-0002-0584-5681
authors.initials: E
authors.lastname: Lalli
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D051567:Proto-Oncogene Proteins c-vav; D054339:Steroidogenic Factor 1; C093651:VAV2 protein, human