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Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells

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Abstract

Tumor invasion and metastasis involve processes in which actin cytoskeleton rearrangement induced by Fascin1 plays a crucial role. Indeed, Fascin1 has been found overexpressed in tumors with worse prognosis. Migrastatin and its analogues target Fascin1 and inhibit its activity. However, there is need for novel and smaller Fascin1 inhibitors. The aim of this study was to assess the effect of compound G2 in colorectal cancer cell lines and compare it to migrastatin in in vitro and in vivo assays. Molecular modeling, actin-bundling, cell viability, inmunofluorescence, migration, and invasion assays were carried out in order to test anti-migratory and anti-invasive properties of compound G2. In addition, the in vivo effect of compound G2 was evaluated in a zebrafish model of invasion. HCT-116 cells exhibited the highest Fascin1 expression from eight tested colorectal cancer cell lines. Compound G2 showed important inhibitory effects on actin bundling, filopodia formation, migration, and invasion in different cell lines. Moreover, compound G2 treatment resulted in significant reduction of invasion of DLD-1 overexpressing Fascin1 and HCT-116 in zebrafish larvae xenografts; this effect being less evident in Fascin1 known-down HCT-116 cells. This study proves, for the first time, the in vitro and in vivo anti-tumoral activity of compound G2 on colorectal cancer cells and guides to design improved compound G2-based Fascin1 inhibitors.

Key messages

• Fascin is crucial for tumor invasion and metastasis and is overexpressed in bad prognostic tumors.

• Several adverse tumors overexpress Fascin1 and lack targeted therapy.

• Anti-fascin G2 is for the first time evaluated in colorectal carcinoma and compared with migrastatin.

• Filopodia formation, migration activity, and invasion in vitro and in vivo assays were performed.

• G2 blocks actin structures, migration, and invasion of colorectal cancer cells as fascin-dependent.

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Acknowledgments

This research was partially supported by the e-infrastructure program of the Research Council of Norway, and the supercomputer center of UiT, the Arctic University of Norway, and by the supercomputing infrastructure of Poznan Supercomputing Center.

Funding

This project received grants from Instituto de Salud Carlos III (Spanish Ministry of Health) and FEDER funds (ref: PI12/1232 and PI15/00626), Spanish Ministry of Economy and Competitiveness MINECO (CTQ2017-87974-R), and by the Fundación Séneca del Centro de Coordinación de la Investigación de la Región de Murcia under Projects 18946/JLI/13 and 20646/JLI/18. BAG belongs to the “Programa de Doctorado en Ciencias de la Salud, Universidad Católica de Murcia (UCAM)” and holds a grant of the UCAM. PCR was supported by Finnish Cultural Foundation Grant (2017-2018).

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Author notes

  1. Silvia Montoro-García and Begoña Alburquerque-González contributed equally to this work.

Authors and Affiliations

  1. Cell Culture Lab. Health Faculty, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain

    Silvia Montoro-García

  2. Pathology and Histology Department. Heatlh Faculty, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos, s/n, Guadalupe, 30107, Murcia, Spain

    Begoña Alburquerque-González & Pablo Conesa-Zamora

  3. Molecular Oncology and TGF-ß Lab, Biomedical Research Institute of Murcia (IMIB-Arrixaca), Carretera Madrid-Cartagena. El Palmar, Murcia, Spain

    Ángel Bernabé-García & Francisco José Nicolás

  4. Telomerase, Cancer and Aging Group, University Clinical Hospital “Virgen de la Arrixaca”, Biomedical Research Institute of Murcia (IMIB-Arrixaca) Murcia, Murcia, Spain

    Manuel Bernabé-García & María Luisa Cayuela

  5. Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, Aapistie 5A, FI-90220, Oulu, Finland

    Priscila Campioni Rodrigues & Tuula Salo

  6. Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland

    Priscila Campioni Rodrigues & Tuula Salo

  7. Eurofins Villapharma Research, Parque Tecnológico de Fuente Álamo. Ctra. El Estrecho-Lobosillo, Km 2,5. Av. Azul E, 30320, Murcia, Spain

    Helena den-Haan

  8. Department of Physical Chemistry and Institute of Biotechnology, University of Granada, Campus Fuentenueva s/n 18071 Granada, Granada, Spain

    Irene Luque

  9. Structural Bioinformatics and High Performance Computing (BIO-HPC) Research Group, Universidad Católica de Murcia (UCAM), Guadalupe, Spain

    Horacio Pérez-Sánchez

  10. Institute of Oral and Maxillofacial Disease, University of Helsinki, Helsinki, Finland

    Tuula Salo

  11. HUSLAB, Department of Pathology, Helsinki University Hospital, Helsinki, Finland

    Tuula Salo

  12. Clinical Analysis Department, Group of Molecular Pathology and Pharmacogenetics, Biomedical Research Institute from Murcia (IMIB), Hospital Universitario Santa Lucía, c/Mezquita sn, 30202, Cartagena, Spain

    Pablo Conesa-Zamora

Authors
  1. Silvia Montoro-García
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  2. Begoña Alburquerque-González
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  3. Ángel Bernabé-García
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  4. Manuel Bernabé-García
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  5. Priscila Campioni Rodrigues
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  6. Helena den-Haan
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  7. Irene Luque
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  9. Horacio Pérez-Sánchez
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  12. Pablo Conesa-Zamora
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Correspondence to Silvia Montoro-García or Pablo Conesa-Zamora.

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Montoro-García, S., Alburquerque-González, B., Bernabé-García, Á. et al. Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer cells. J Mol Med 98, 383–394 (2020). https://doi.org/10.1007/s00109-020-01877-z

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