Vimentin and Cancer: the Control of Cell Adhesion, Mechanics and Motility

Il 12/06/2017 ore 14.30 - 15.30

Sala Conferenze, Area della ricerca Na1, via P. Castellino, 111 80131 Napoli

Annica KB Gad, from the Karolinska Institutet, Stockholm, Sweden, will give a seminar on the role of vimentin in cancer progression.

Metastasising tumour cells show increased levels of the intermediate filament protein vimentin, which therefore for decades has been used to diagnose invasive tumours in the clinic. Recent findings suggest that vimentin is not only a passive marker of carcinoma, but also may induce tumour cell invasion (1). Gad's team hypothesised that increased levels of vimentin controls focal adhesions and cell migration, and analysed metastasising cells with or without overexpression of vimentin, using three-color, 30 nm resolution STED microscopy, TIRF and confocal microscopy. The data suggest that vimentin filaments localises at the base of large focal adhesions, controls the size of these adhesions and promotes an elongated cell shape (2).

Annica Gad and her group also found that oncogenes induce an increased density of nanoscale adhesions in cell and a collapse of the vimentin network, detected at the nanoscale level as a reduced parallel arrangement and increased width of the fibres. Expression of oncogenes also resulted in increased levels of the tubulin deacetylase HDAC6 and altered spatial distribution of acetylated microtubules. Oncogene-expression also increased cellular stiffness and promoted the invasive capacity of the cells. HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of oncogene-expressing cells (3). Taken together, these data suggest that oncogenes can induce cellular stiffness via an HDAC6-mediated reorganisation of the vimentin filament network.

During tumour development, fibroblasts that initially inhibit tumour growth in the tumour microenvironment may lose their inhibitory capacity and even become tumour stimulatory. The molecular mechanism underlying this transformation into cancer-associated fibroblasts is not clear. We created RhoA gene - knockout fibroblasts and found that the cells had lost the capacity to inhibit tumour growth in vitro, and promoted tumour growth in vivo. These tumour-promoting fibroblasts showed loss of wide actin stress fibres and large focal adhesions, and a reorganised vimentin intermediate filament network. The fibroblasts also showed reduced contractile forces and an increased stiffness, as compared to control (4). These findings suggest that cytoskeletal changes alter the adhesive and mechanical properties of fibroblasts, which thereby gain the capacity to promote tumour growth.

Taken together, these findings – that key factors in cancer, such as oncogenes, HDAC6 and cancer-promoting fibroblasts change the vimentin network and cell mechanics – highlights the need for further investigations of both vimentin and the mechanical properties of cells to better understand the mechanisms behind tumour and metastasis formation.

 

References:

1. FASEB J. 2010. Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition. Mendez MG1, Kojima S, Goldman RD.

2. Cells. 2017. Vimentin Levels and Serine 71 Phosphorylation in the Control of Cell-Matrix Adhesions, Migration Speed, and Shape of Transformed Human Fibroblasts. Terriac E, Coceano G, Mavajian Z, Hageman TA, Christ AF, Testa I, Lautenschläger F, Gad AK.

3. PNAS. 2014 Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness. Rathje LS1, Nordgren N, Pettersson T, Rönnlund D, Widengren J, Aspenström P. Gad AK.

4. PNAS. 2017. RhoA knockout fibroblasts lose tumor-inhibitory capacity in vitro and promote tumor growth in vivo. Alkasalias T, Alexeyenko A, Hennig K, Danielsson F, Lebbink RJ, Fielden M, Turunen SP, Lehti K, Kashuba V, Madapura HS, Bozoky B, Lundberg E, Balland M, Guvén H, Klein G, Pavlova T, Gad AK. (T.P and A.G. contributed equally to this work)

Organizzato da:
Ibp - Cnr

Referente organizzativo:
Alberto Luini
Cnr - Istituto di biochimica delle proteine
Via P. Castellino, 111 80131 Napoli
a.luini@ibp.cnr.it
081/6132722

Modalità di accesso: ingresso libero