Loss of type III transforming growth factor β receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression

Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (T beta RIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, T beta RIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of T beta RIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining T beta RIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous T beta RIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of T beta RIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of T beta RIII, generating soluble T beta RIII (sT beta RIII). In human pancreatic cancer specimens, T beta RIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of T beta RIII expression during the EMT of pancreatic cancer progression, with a specific role for sT beta RIII in suppressing EMT-associated increases in motility and invasion.