Dosage-Dependent Transcriptional Regulation of VAV2 By Steroidogenic Factor-1 Drives Adrenocortical Carcinoma Cell Invasion and Malignancy

Presentation Number: OR01-3
Date of Presentation: April 3rd, 2017

Carmen Ruggiero1, Mabrouka Doghman1, Silviu Sbiera2, Iuliu Sbiera2, Maddy Parsons3, Bruno Ragazzon4, Aurélie Morin5, Estelle Robidel5, Judith Favier5, Jerome Yves Bertherat6, Martin Fassnacht2 and Enzo Lalli*1
1IPMC CNRS UMR 7275, Valbonne, France, 2University Hospital Wuerzburg, Wuerzburg, Germany, 3King's College, London, United Kingdom, 4INSERM U 1016, CNRS 8104, Institut Cochin, Paris Descartes University, Paris, France, 5Inserm U970, Paris, France, 6APHP - Hôpital Cochin Université Paris Descartes, Paris, France

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. Recent studies have shown only a limited efficacy of current polychemotherapeutic regimens or targeted therapies in advanced-stage ACC. New hopes for more efficient treatments for ACC stem from recent discoveries that have identified important molecular actors implicated in its pathogenesis. Those include the transcription factor SF-1 (Steroidogenic Factor 1)/NR5A1, a nuclear receptor that has a key role in adrenocortical development and regulation of steroidogenesis. Our previous studies revealed that SF-1 overexpression triggers increased proliferation in human H295R ACC cells and induces adrenocortical tumorigenesis in Sf-1 transgenic mice (1, 2). Furthermore, SF-1 overexpression is associated with poor clinical outcome in ACC and represents a stage-independent prognostic marker (3).

SF-1 overexpression in ACC cells induces relevant modifications of gene expression, not only affecting its classical steroidogenic target genes but also a variety of genes involved in other physiological processes and signaling pathways (4). It is remarkable that some of those changes mirror similar changes in gene expression found in ACC compared to benign adrenocortical tumors and normal adrenal cortex tissue. These data validated the use of our cellular model as a discovery platform for new factors involved in the definition of the malignant phenotype in ACC.

In the study presented here we show that an increased SF-1 dosage in H295R cells increased activation of the small GTPases Rac1 and Cdc42, triggered cytoskeleton remodeling and increased their invasive capacities in vitro in the Matrigel invasion assay and in vivo in the chicken chorioallantoic membrane (CAM) assay. RNA interference experiments demonstrated that SF-1 dosage dependent expression of VAV2, which encodes a guanine nucleotide exchange factor (GEF), has a critical role in the regulation of those phenotypes. Consistently with these results, tumor VAV2 mRNA and protein expression was significantly correlated to prognosis in three different ACC patient cohorts. A multivariate model adjusted for tumor stage, sex, age and resection status of the tumors confirmed the high prognostic role of VAV2 on ACC patient relapse and overall survival (adjusted HR for relapse: 5.84 95%CI: 2.19-15.59, p<0.0001 and adjusted HR for death: 2.24 95%CI: 1.21-4.13, p=0.010).

These results identify VAV2 as an important factor driving malignancy and potentially druggable target in ACC.

 

Nothing to Disclose: CR, MD, SS, IS, MP, BR, AM, ER, JF, JYB, MF, EL