PUBLICATION
FSCN1 as a new druggable target in adrenocortical carcinoma
- Authors
- Ruggiero, C., Tamburello, M., Rossini, E., Zini, S., Durand, N., Cantini, G., Cioppi, F., Hantel, C., Kiseljak-Vassiliades, K., Wierman, M.E., Landwehr, L.S., Weigand, I., Kurlbaum, M., Zizioli, D., Turtoi, A., Yang, S., Berruti, A., Luconi, M., Sigala, S., Lalli, E.
- ID
- ZDB-PUB-230329-38
- Date
- 2023
- Source
- International Journal of Cancer 153(1): 210-223 (Journal)
- Registered Authors
- Lalli, Enzo
- Keywords
- adrenocortical carcinoma, cytoskeleton, endocrine cancer
- MeSH Terms
-
- Adrenal Cortex Neoplasms*/drug therapy
- Adrenal Cortex Neoplasms*/genetics
- Adrenal Cortex Neoplasms*/metabolism
- Adrenocortical Carcinoma*/drug therapy
- Adrenocortical Carcinoma*/genetics
- Adrenocortical Carcinoma*/metabolism
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Gene Expression Regulation, Neoplastic
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Zebrafish
- PubMed
- 36971100 Full text @ Int. J. Cancer
Citation
Ruggiero, C., Tamburello, M., Rossini, E., Zini, S., Durand, N., Cantini, G., Cioppi, F., Hantel, C., Kiseljak-Vassiliades, K., Wierman, M.E., Landwehr, L.S., Weigand, I., Kurlbaum, M., Zizioli, D., Turtoi, A., Yang, S., Berruti, A., Luconi, M., Sigala, S., Lalli, E. (2023) FSCN1 as a new druggable target in adrenocortical carcinoma. International Journal of Cancer. 153(1):210-223.
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. This article is protected by copyright. All rights reserved.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping