SMAD1 and cancer: Interestingly, phosphorylation of Smad1/5 at Ser463/465, which has been implicated in epithelial-mesenchymal transition [29, 30], was obviously induced in cancer cells by CAFs-derived CM, suggesting CAFs might be able to exert pro-metastatic role via LRG1-mediated activation of Smad1/5 signaling (Fig. 3d).