Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence.
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.
Ansieau
Stéphane
S
Inserm, U590, Lyon F-69008, France.
Bastid
Jeremy
J
Doreau
Agnès
A
Morel
Anne-Pierre
AP
Bouchet
Benjamin P
BP
Thomas
Clémence
C
Fauvet
Frédérique
F
Puisieux
Isabelle
I
Doglioni
Claudio
C
Piccinin
Sara
S
Maestro
Roberta
R
Voeltzel
Thibault
T
Selmi
Abdelkader
A
Valsesia-Wittmann
Sandrine
S
Caron de Fromentel
Claude
C
Puisieux
Alain
A
D000818:Animals; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence / Q000235:genetics; D004285:Dogs; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000378:metabolism; D014162:Transfection; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D009687:Nuclear Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C103173:TWIST1 protein, human; C486274:TWIST2 protein, human; D016159:Tumor Suppressor Protein p53; D051879:Twist-Related Protein 1; D018631:ras Proteins