Abstract
Twist1 and Twist2 are related transcription factors that play major roles both during embryonic development and in several pathologies, including cancer. Twists' oncogenic potential arises from a combination of their multiple functions in development. Notably, both Twist induce epithelial-to mesenchymal transition, thus promoting tumour invasiveness and possibly conferring to cells self-renewal properties. Furthermore, through disruption of both Rb- and p53-driven pathways, Twist override two major oncogene-induced fail-safe programs, namely senescence and apoptosis, thereby promoting malignant conversion. Twist has also been reported to participate in acquisition of drug resistance and in promotion of neo-angiogenesis.Current knowledge of pleiotropic activities of Twist prompted us to postulate that these factors may be major regulators of stress response. Cancer cells survive and grow within a continuously changing environment that creates multiple stresses to which they must adapt in order to survive and strive. Such adaptations often give rise to the acquisition of an aggressive phenotype. Consistent with this hypothesis, we recently unveiled new activities of Twist proteins that are related to stress response. We have shown that Twist regulates response to oxidative stress, a condition exacerbated in cancer by stimuli such as inflammation, increased cellular metabolism and changes in tumour oxygenation. Our work has contributed to the understanding of molecular mechanisms through which Twist diminishes cellular ROS and thus participates in the escape from apoptosis and senescence. In the first part of my thesis, I worked on the antioxidant activity of Twist and described its molecular mechanisms.The second part of my work addressed the impact of Twist proteins on cellular response to hypoxia that is insufficient oxygen supply, frequently found in solid tumours. Cellular response to hypoxic stress relies on stabilization and activation of HIF1α, a key transcriptional mediator of the hypoxic response, regulating numerous genes involved in glucose metabolism, oxygen transport, angiogenesis, cell growth and apoptosis. HIF1α is beneficial for cancer cells in response to short hypoxic episodes, however its sustained activation in case of prolonged hypoxia may push cancer cells towards apoptosis. In this context, we have shown that Twist protects cancer cells from hypoxia-induced apoptosis. We have discovered HIF1α and Twist physically interact, suggesting a possible mechanistic basis for Twist's protective effect. These results led us to postulate that Twist plays a role in cellular response to hypoxia and thus participates in cancer cell adaptation and acquisition of aggressive phenotypes triggered by lack of oxygen.Our results reinforce the notion that Twist factors are major cellular stress modulators that might be important for adaptation of cancer cells to changing conditions in the process of tumour progression.