Actin stress fibers-mediated cell stiffening promotes the proliferation of pre-invasive breast cancer cells

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Actin stress fibers-mediated cell stiffening promotes the proliferation of pre-invasive breast cancer cells

Friday, 16.06.2017

In this study recently published in Nature Communications, the authors use a human breast cell line with conditional Src induction, breast tumor lesions and the in vivo model Drosophila melanogaster to show that cells undergo an actin stress fiber-mediated cell stiffening state prior to acquiring malignant features. This state promotes ERK-dependent cell proliferation, as well as, the progression towards a fully transformed state. This study was conducted at the Instituto Gulbenkian de Ciência in collaboration with the Instituto de Investigação e  Inovação em Saúde (i3S), Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Faculty of Medicine of the University of Porto (Portugal), Biotechnology Center from the Technische Universität Dresden (Germany), and  Ophiomics – Precision Medicine (Portugal).



Sandra Tavares1, André Filipe Vieira2,3,*, Anna Verena Taubenberger4,*, Margarida Araújo1,*, Nuno Pimpao Martins1, Catarina Brás-Pereira 1, António Polónia2,3,5, Maik Herbig4, Clara Barreto1, Oliver Otto4, Joana Cardoso1,6, José B. Pereira-Leal1,6, Jochen Guck4, Joana Paredes2,3,7 & Florence Janody1

(1) Instituto Gulbenkian de Ciência, Rua da Quinta Grande 6, P-2780-156 Oeiras, Portugal

(2) Epithelial Interactions in Cancer group, Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Rua Alfredo Allen, 208, 4200-393 Porto, Portugal.

(3) Cancer Genetics group, Instituto de Patologia e Imunologia Molecular da Universidade do Porto (Ipatimup), Rua Julio Amaral de Carvalho 45, 4200–135 Porto, Portugal.

(4) Biotechnology Center, Technische Universität Dresden, Tatzberg 47/49, 01307 Dresden, Germany.

(5) Department of Pathology, Ipatimup Diagnostics, Ipatimup, Rua Dr Roberto Frias s/n, 4200–465 Porto, Portugal.

(6) Ophiomics – Precision Medicine, Rua Cupertino de Miranda 9, lote 8, 1600-513 Lisboa, Portugal

(7) Department of Pathology, Faculty of Medicine, University of Porto, Alameda Prof. Hernaani Monteiro, 4200–319 Porto, Portugal.

Studies of the role of actin in tumor progression have highlighted its key contribution in cell softening associated with cell invasion. Here, using a human breast cell line with conditional Src induction, we demonstrate that cells undergo a stiffening state prior to acquiring malignant features. This state is characterized by the transient accumulation of stress fibers and upregulation of Ena/VASP-like (EVL). EVL, in turn, organizes stress fibers leading to transient cell stiffening, ERK-dependent cell proliferation, as well as, enhances Src activation and the progression towards a fully transformed state. Accordingly, EVL accumulates predominantly in pre-malignant breast lesions and is required for Src-induced epithelial overgrowth in Drosophila. While cell softening allows for cancer cell invasion, our work reveals that stress fiber-mediated cell stiffening could drive tumor growth during pre-malignant stages. A careful consideration of the mechanical properties of tumor cells could therefore offer new avenues of exploration when designing cancer-targeting therapies.


Journal: Nature Communications

http://www.nature.com/articles/ncomms15237