(A) A monolayer of epithelial cells with polygonal morphology is held in formation by cell-cell contact between neighboring cells via molecules such as E-cadherin, as well as by the interaction of cell-surface integrins with proteins in the basement membrane. (B) In this issue of the JCI, Lee et al. (15) show that overexpression of TM4SF5 in human hepatocarcinoma SNU449 cells results in phenotypic changes in these cells that resemble EMT, such as an elongated morphology, loss of cell-cell contact, and loss of contact inhibition, resulting in overgrowth. (C) Lee et al. (15) provide data indicating that TM4SF5 overexpression enhances the expression and cytosolic stability of p27^Kip1, likely via kinase interacting with stathmin– (KIS-) and/or Akt-mediated phosphorylation. This results in RhoA inhibition and subsequent changes in cell morphology resembling EMT. The authors observed decreased expression of ZO-1 and E-cadherin (the latter occurring in a Snail1-independent manner) and increased α-SMA expression. Loss of cell-cell contact leads to loss of contact inhibition between cells and uncontrolled multilayer growth. Importantly, this uncontrolled growth could be blocked by suppression of TM4SF5 or p27^Kip1, Rho activation, or E-cadherin reexpression in these cells. Upon subcutaneous injection of TM4SF5-overexpressing SNU449 cells into nude mice, Lee et al. observed tumor formation. Figure modified from ref. 15.