ASK-ing EMT not to spread cancer.

G lobal communication by the epithelial cell layer is maintained through gap junctional complexes, separated from adjacent tissues by a basal lamina. Mesenchymal cells are loosely organized in a three-dimensional extracellular matrix, comprising connective tissue adjacent to the stroma. Conversion of epithelial cells to mesenhymal cells involves profound phenotypic changes, including loss of cellcell adhesion, loss of cell polarity, and the acquisition of migratory and invasive properties (1). The process of epithelial-mesenchymal transition (EMT) is a critical event during embryonic development, required for morphogenetic movements during gastrulation and organ formation, but also a convenient venue for epithelial-derived tumors to become invasive and rapidly metastasize (2, 3). EMT endows cells with migratory and invasive properties, induces stem cell properties, and prevents apoptosis and senescence, thus orchestrating the initiation of metastasis (3, 4). Loss of epithelial-cell markers (E-cadherin, β-catenin) and gain of mesenchymal-cell markers (N-cadherin, vimentin), at the leading edge or invasive front of solid tumors, is associated with progression to metastasis (3). To preserve cellular shape and polarity, the intracellular domains of cadherins connect to the actin cytoskeleton through α-catenin and β-catenin. It is the signaling activities of mesenchymal cells that facilitate migration and survival in an anchorage-independent environment (2, 3). Thus even if there is no histological evidence of cellular intermediates during the transition, activation of mesenchymal genes in epithelial cells is critical for EMT success. The contribution of a tumor-suppressor gene’s activity to EMT is a fresh determinant in the EMT landscape. In this issue of PNAS, Xie et al. (5) report a unique player in the mechanistic control of EMT, the tumor suppressor gene DAB2IP (also known as ASK1-interacting protein-1), loss of which facilitates EMT leading to metastasis. The documented function of DAB2IP as a scaffold protein in modulating EMT via GSK-3β-catenin recognizes a different “operating forum” for tumor-suppressor action and raises important questions about the dual role of β-catenin in EMT: Not only does it enhance cell-cell adhesion by associating with E-cadherin complexes in adherent junctions, it also functions as a transcriptional coactivator after interacting with TCF/LEF transcription-factor complexes. Indeed, growing evidence suggests that β-catenin-mediated transcription induces Slug or Twist gene expression that further represses E-cadherin, thus contributing to EMT (6, 7). The primary physiological significance of the article by Xie et al. relates to the observation that restoring DAB2IP in metastatic prostate cancer cells reversed EMT, and loss of this tumor suppressor in human cancer cells leads to distant metastatic spread. The findings show that DAB2IP functions as a scaffold protein in regulating EMT by modulating nuclear β-catenin/TCF activity. Prostate epithelial cells can undergo EMT in response to an array of soluble growth factors, including TGFβ1, EGF, IGF1, β2microglobulin (β2-m), or exposure to a bone microenvironment (8, 9). TGF-β represents a potent EMT inducer in normal development and tumor progression (8), via Smad-dependent and -independent transcriptional pathways. Smad-mediated induction of Snail, Slug, and Twist via high motility group A2 (HMGA2) (7) and Smad-independent phosphorylation of Par6 contribute to dissolution of cell junction complexes (10, 11) (Fig. 1). But how can one argue that the propensity of a tumor suppressor to change the state of movement and shape of the cell in its microenvironment leads to its instant acquisition of a therapeutic value in targeting metastastic prostate cancer? The answer lies in the link between EMT and tumor progression to metastasis. In prostate cancer, androgens can suppress E-cadherin expression and induce mesenchymal marker expression. EMT activation may result in increased bone turnover, implicated in bone colonization in Fig. 1. EMT regulation in prostate cancer cells. Loss of expression of E-cadherin, a key participant in calcium-dependent interactions which form epithelial adherent junctions, is the principal characteristic of EMT. In response to TGFβ1, Smad-mediatedEMTproceeds via induction of Snail, Slug, and Twist, and Smadindependent phosphorylation of Par6 contributes to the dissolution of cell junction complexes via Smurf. Snailbinds to E-cadherin promoter and represses its transcription during EMT. E-cadherin repressors induce EMTby regulatingexpressionof genes repressing the epithelial character andpromoting themesenchymal state (AR). DAB12P controls epithelial cell movement and survival, stopping EMT. AJ, adherent junctions.