FSCN1 as a new druggable target in adrenocortical carcinoma

Carmen Ruggiero, Mariangela Tamburello, Elisa Rossini, Silvia Zini, Nelly Durand, Giulia Cantini, Francesca Cioppi, Constanze Hantel, Katja Kiseljak-Vassiliades, Margaret E. Wierman, Laura Sophie Landwehr, Isabel Weigand, Max Kurlbaum, Daniela Zizioli, Andrei Turtoi, Shengyu Yang, Alfredo Berruti, Michaela Luconi, Sandra Sigala, Enzo Lalli

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a high risk of relapse and metastatic spread. The actin-bundling protein fascin (FSCN1) is overexpressed in aggressive ACC and represents a reliable prognostic indicator. FSCN1 has been shown to synergize with VAV2, a guanine nucleotide exchange factor for the Rho/Rac GTPase family, to enhance the invasion properties of ACC cancer cells. Based on those results, we investigated the effects of FSCN1 inactivation by CRISPR/Cas9 or pharmacological blockade on the invasive properties of ACC cells, both in vitro and in an in vivo metastatic ACC zebrafish model. Here, we showed that FSCN1 is a transcriptional target for β-catenin in H295R ACC cells and that its inactivation resulted in defects in cell attachment and proliferation. FSCN1 knock-out modulated the expression of genes involved in cytoskeleton dynamics and cell adhesion. When Steroidogenic Factor-1 (SF-1) dosage was upregulated in H295R cells, activating their invasive capacities, FSCN1 knock-out reduced the number of filopodia, lamellipodia/ruffles and focal adhesions, while decreasing cell invasion in Matrigel. Similar effects were produced by the FSCN1 inhibitor G2-044, which also diminished the invasion of other ACC cell lines expressing lower levels of FSCN1 than H295R. In the zebrafish model, metastases formation was significantly reduced in FSCN1 knock-out cells and G2-044 significantly reduced the number of metastases formed by ACC cells. Our results indicate that FSCN1 is a new druggable target for ACC and provide the rationale for future clinical trials with FSCN1 inhibitors in patients with ACC.

Original languageEnglish (US)
Pages (from-to)210-223
Number of pages14
JournalInternational Journal of Cancer
Volume153
Issue number1
DOIs
StatePublished - Jul 1 2023

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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