Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition

The type III TGF-beta receptor (T beta RIII) is a TGF-beta co-receptor that presents ligand to the type II TGF-beta receptor to initiate signaling. T beta RIII also undergoes ectodomain shedding to release a soluble form (sT beta RIII) that can bind ligand, sequestering it away from cell surface receptors. We have previously identified a T beta RIII extracellular mutant that has enhanced ectodomain shedding (super shedding (SS)-T beta RIII-SS). Here, we utilize T beta RIII-SS to study the balance of cell surface and soluble T beta RIII in the context of lung cancer. We demonstrate that expressing T beta RIII-SS in lung cancer cell models induces epithelial-to-mesenchymal transition (EMT) and that these T beta RIII-SS (EMT) cells are less migratory, invasive and adhesive and more resistant to gemcitabine. Moreover, T beta RIII-SS (EMT) cells exhibit decreased tumorigenicity but increased growth rate in vitro and in vivo. These studies suggest that the balance of cell surface and soluble T beta RIII may regulate a dichotomous role for T beta RIII during cancer progression.