Cell Migration Gateway (November 2009)

Cancer biology: The benefit of being single
Cell Migration Gateway (November 2009) | doi:10.1038/cmg105
StandfirstTGFβ signalling drives single cell motility and stimulates haematogenic metastasis in breast cancer cells.


In vivo image of mammary carcinoma cells showing cancer cells in green, lymphatic vessel in red and collagen in blue.

Image courtesy of Dr. Erik Sahai, Cancer Research UK London Research Institute, London, UK.
Regulation of cell motility and invasion is important for the dissemination of tumour cells from their primary location to lymph or blood vessels during metastasis. The epithelial to mesenchymal transition of cancer cells leads to increased cell motility and tumour progression, and is known to involve transforming growth factor β (TGFβ). In Nature Cell Biology, Erik Sahai and colleagues now report that the transient and local activation of TGFβ signalling in breast cancer cells switches them from cohesive movement to single cell motility and promotes haematogenous metastasis.

Using intravital imaging of mammary carcinoma cells, the authors show that only 5 % of primary tumour cells were motile and that they moved either singly or collectively. Interestingly, motile behaviour was not maintained in lymph node metastases. Imaging of fluorescent reporter genes demonstrated that TGFβ is active primarily in single cells and that this correlates with the nuclear localization of Smad2 and Smad3, which are phosphorylated by TGFβ and form a complex with Smad4 that accumulates in the nucleus. Importantly, the increase in TGFβ activity was not maintained in lymph node and lung metastases, suggesting that TGFβ is only activated transiently.

So, how does the activity of TGFβ affect the mode of tumour cell migration? When cultured in the presence of TGFβ, tumour cells moved singly instead of growing in colonies. This was inhibited by knockdown of Smad4, suggesting a role for TGFβ-mediated transcription in determining the mode of migration. Using microarray analysis, Erik Sahai and colleagues identified several genes, which are upregulated in the cells treated with TGFβ. Knockdown studies revealed that these genes have distinct roles in the switch from collective to single cell motility, suggesting that TGFβ activates a programmed transcriptional mechanism to influence cell motility.

Intravital imaging also revealed that expression of a 'dominant-negative' TGFβ receptor in rat breast cancer cells triggered a switch back to cohesive movement, whereas overexpression of TGFβ promoted single cell motility. This suggests that TGFβ is necessary for single cell motility in vivo. But how does this switch in cell motility affect metastasis?

The authors confirmed that cells lacking TGFβ signalling were moving collectively and could only enter lymphatic vessels to disseminate into the lymph nodes. Conversely, cells with permanently hyperactive TGFβ signalling entered the blood efficiently, but were ineffective at forming lung metastases as prolonged TGFβ signalling inhibited growth. Thus, the transient activation of TGFβ enables single cells to enter the blood and its subsequent inactivation permits growth at secondary sites.

This study demonstrates that dynamic TGFβ signalling regulates both the mode of migration and the metastatic route of breast cancer cells. Future studies will hopefully further elucidate the distinct mechanisms for lymphatic and haematogenic metastasis.

Author: Iley Ozerlat

Original Research Paper
Giampieri , S. et al. Localised and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biology. published online 18 October 2009.
doi: 10.1038/ncb1973 | Article |
Further Reading
TGFβ-SMAD signal transduction: molecular specificity and functional flexibility. Schmierer , B. & Hill , C. S. Nature Reviews Molecular Cell Biology. 8, 970–982 (2007) | doi:10.1038/nrm2297 | Article |