Induction of EMT by Twist Proteins as a Collateral Effect of Tumor-Promoting Inactivation of Premature Senescence

• Published in: Cancer cell 2008-07, Vol.14 (1), p.79-89
• Main Authors: Ansieau, Stéphane, Bastid, Jeremy, Doreau, Agnès, Morel, Anne-Pierre, Bouchet, Benjamin P., Thomas, Clémence, Fauvet, Frédérique, Puisieux, Isabelle, Doglioni, Claudio, Piccinin, Sara, Maestro, Roberta, Voeltzel, Thibault, Selmi, Abdelkader, Valsesia-Wittmann, Sandrine, Caron de Fromentel, Claude, Puisieux, Alain
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Transdifferentiation - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; CELLBIO; Cellular Senescence - genetics; Dogs; Enzyme Activation; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fibroblasts - enzymology; Fibroblasts - metabolism; Fibroblasts - pathology; Gene Expression Regulation, Neoplastic; Humans; HUMDISEASE; Mammary Glands, Human - metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Nude; Mice, Transgenic; Neoplasm Invasiveness; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; ras Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Retinoblastoma Protein - metabolism; RNA Interference; SIGNALING; Transfection; Transplantation, Heterologous; Tumor Suppressor Protein p53 - metabolism; Twist-Related Protein 1 - genetics; Twist-Related Protein 1 - metabolism; Up-Regulation
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2008.06.005

Twist1 and Twist2 are major regulators of embryogenesis. Twist1 has been shown to favor the metastatic dissemination of cancer cells through its ability to induce an epithelial-mesenchymal transition (EMT). Here, we show that a large fraction of human cancers overexpress Twist1 and/or Twist2. Both proteins override oncogene-induced premature senescence by abrogating key regulators of the p53- and Rb-dependent pathways. Twist1 and Twist2 cooperate with Ras to transform mouse embryonic fibroblasts. Interestingly, in epithelial cells, the oncogenic cooperation between Twist proteins and activated mitogenic oncoproteins, such as Ras or ErbB2, leads to complete EMT. These findings suggest an unanticipated direct link between early escape from failsafe programs and the acquisition of invasive features by cancer cells.