Scientists from University of Oxford have indicated that a new-found anti-cancer protein named ASPPS could control and reverse epithelial cells’ changes of shape and motion state. This finding would be very important in the study of wound healing, embryonic development, and cancer metastasis. This study was published in Nature Cell biology.

Epithelial to mesenchymal transition(EMT) and the reverse, mesenchymal to epithelial transition(MET), provide cellular plasticity during development, wound healing and cancer metastasis. EMT is associated with enhanced cell migration and invasion and requires a disruption of apical-basal polarity and loss of E-cadherin expression. MET is required for nephrogenesis, and defects in MET result in kidney fibrosis. In addition, ASPP2 was first identified as a tumor suppressor and an activator of the p53 family. Its downregulation is associated with metastasis of human breast cancer and head and neck cancer, and poor prognosis in diffuse large B-cell lymphomas.

In this study, researchers have identified ASSP2 as a molecular switch of MET and EMT.ASPP2 contributes to MET in mouse kidney in vivo. Mechnistically, ASPP2 induces MET through its PAR3-binding amino-terminus, independently of p53 binding. ASPP2 prevents β-catenin from transactivating ZEB1, directly by forming an ASPP2-β-catenin-E-cadherin ternary complex and indirectly by inhibiting β-catenin’s N-terminal phosphorylation to stabilize the β-catenin-E-cadherin ternary complex. ASSP2 limits the pro-invasive property of oncogenic RAS and inhibits tumour metastasis in vivo. Reduced ASSP2 expression results in EMT, and is associated with poor survival in hepatocellular carcinoma and breast cancer patients.

Therefore, ASPP2 is a key regular of epithelial plasticity that connects cell polarity to the suppression of WNT signaling, and tumor metastasis.

Reference:

Wang Y, Bu F, Royer C, et al. ASPP2 controls epithelial plasticity and inhibits metastasis through β-catenin-dependent regulation of ZEB1[J]. Nature cell biology, 2014.