Abstract
BackgroundMetastasis is a process where only a small subset of cells is capable of successfully migrating to and propagating at secondary sites. TGF-β signalling is widely known for its role in cancer metastasis and is associated with cell migration in whole cell populations.FindingsWe extend these findings by investigating the role of TGF-β signalling in promoting migration and motility by imaging the signalling activity in live, individual MDA-MB-231 cancer cells utilizing a novel Smad3 Td-Tomato reporter adenovirus. Here we find that not all MDA-MB-231 cancer cells have similar TGF-β mediated Smad3 transcription activity and display at least two distinct migratory populations. Importantly, Smad3 activity was significantly higher within migratory cells compared to non-migrated cells in wound healing and transwell assays. Furthermore, time-lapse experiments showed that MDA-MB-231 cells displaying Smad3 activity moved faster and a greater distance compared to cells not displaying Smad3 reporter activity. Interestingly, despite being more motile than cells with undetectable levels of Smad3 activity, high Smad3 activity was detrimental to cell motility compared to low and medium level of Smad3 activity.ConclusionsWe have developed a method enabling real-time visualization of TGF-β signalling in single live cells. Breast cancer cell motility and migration is driven by sub-populations of cells with dynamic TGF-β-Smad3 activity. Those sub-populations may be responsible for tumor invasion and metastasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0309-1) contains supplementary material, which is available to authorized users.
Highlights
Metastasis is a process where only a small subset of cells is capable of successfully migrating to and propagating at secondary sites
Breast cancer cell motility and migration is driven by sub-populations of cells with dynamic Transforming Growth Factor-β (TGF-β)-Smad3 activity
Cells with increased TGF-β signalling activity exhibit enhanced wound healing Time-lapse microscopy studies showed that MDA-MB-231 cells moved an overall greater distance when stimulated by TGF-β (Figure 1A(ii))
Summary
Metastasis is a process where only a small subset of cells is capable of successfully migrating to and propagating at secondary sites. Luwor et al Molecular Cancer (2015) 14:50 drives metastasis in animal models [15,16,17]. These observations have been made by assessing the effect of TGF-β across the global, overall tumour population. We expand on these findings in this current study to determine the effect of real-time TGF-β signalling while tracking live single cell movement
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