Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways.
Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contacts-an early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whereas the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness, and anoikis resistance. We find the E-cadherin binding partner beta-catenin to be necessary, but not sufficient, for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss-induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes.
Onder
Tamer T
TT
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Gupta
Piyush B
PB
Mani
Sendurai A
SA
Yang
Jing
J
Lander
Eric S
ES
Weinberg
Robert A
RA
D000818:Animals; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D002450:Cell Communication; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008954:Models, Biological; D009362:Neoplasm Metastasis; D015398:Signal Transduction; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000378:metabolism
D015820:Cadherins; D051879:Twist-Related Protein 1