Twist, as a failsafe program escape, directs the tumour outcome.

Image courtesy of Dr Alain Puisieux, Inserm, U590, Lyon, France.

TWIST transcription factors are important regulators of embryogenesis. Reporting in Cancer Cell, Alain Puisieux and colleagues now show that the two closely related mammalian TWIST factors cooperate with oncoproteins to inhibit cellular senescence and promote cancer dissemination by inducing epithelial-mesenchymal transition (EMT).

TWIST1 has been previously associated with tumour progression and metastasis. The authors report that TWIST2 was also strongly upregulated in developing tumours in a mouse model of mammary cancer. Consistently, both TWIST1 and TWIST2 mRNA were overexpressed in a variety of primary human tumours and tumour-derived cell lines tested.

To determine their oncogenic properties, the authors silenced the TWIST genes in both murine and human cancer cell lines. Remarkably, TWIST depletion triggered cellular senescence, suggesting that TWIST induction in vivo might override oncogene-induced senescence — a major safeguard mechanism that prevents cancer progression.

The authors then analysed how TWIST function relates to that of oncogenes such as Ras. It is well known that constitutive activation of the Ras-Raf mitogenic pathway results in growth arrest and premature senescence. However, when the authors expressed either TWIST1 or TWIST2 together with activated Ras in mouse embryo fibroblasts (MEFs), senescence was inhibited and cells continued to proliferate. Furthermore, MEFs with both active Ras and TWIST showed malignant transformation properties and were highly tumourigenic when grafted into nude mice, leading to the formation of aggressive sarcomas.

But how could TWIST proteins inhibit oncogene-induced safeguard programmes? The authors found that induction of the cyclin-dependent kinase inhibitors p16 and p21 was abrogated upon TWIST1 or TWIST2 expression in MEFs infected with active Ras. As p21 and p16 function in the p53 and Retinoblastoma (Rb) tumour-suppressor pathways, TWIST proteins may cooperate with Ras to prevent cell-cycle arrest by disrupting these pathways.

Earlier studies report that ectopic expression of TWIST1 induces partial EMT in mammary epithelial cells, and a similar effect was confirmed for TWIST2. However, whereas TWIST proteins alone induced only partial acquisition of mesenchymal features, cells expressing both TWIST1 or TWIST2 and active Ras were able to undergo complete EMT.

Together, these data show two novel and unexpected levels of cooperation between mitogenic oncoproteins and TWIST proteins. On one hand, TWIST enables tumour cells to override premature senescence and, on the other hand, TWISTs and oncoproteins cooperate to induce EMT, thus favouring metastatic dissemination.

Author: Kim Baumann