Microtubule-mediated nuclear deformation drives the Epithelial-to-Mesenchymal Transition and breast cancer.

The Epithelial-to-Mesenchymal transition (EMT) is a cell state change essential for the development and homeostasis of all metazoan organisms. EMT-like programmes also drive metastasis in tumour cells. Classical studies have demonstrated that mechanical and geometric cues, such as the disruption of cell-cell adhesion can induce EMT. But how these cues are converted into cell fate decisions through changes in transcriptional activity are not well understood. Using an image-omic approach we identify Junctional Adhesion Molecule 3 (JAM3) as a tumour suppressor in breast cancer patients, and a suppressor of EMT in breast epithelial cells. Engagement of EMT following JAM3 depletion is due to changes in nuclear shape caused by microtubules, and resulting activation of pro-EMT factors such as YAP and TAZ. Critically, uncoupling microtubules from the nucleus reverts EMT. These results provide a mechanistic basis for the long-standing observations of how loss of cell-cell adhesion leads to EMT and cancer.