Notch signaling in human cancers: molecular mechanisms and clinical translation

Human cancer progression is a complex multi-factorial process that is associated with the emergence of cells with features that are typically attributed to the malignant process. However, the emergence of cancer reflects in some sense the overall consequences of the aberrant responses of the immune system, neighbouring stromal cells etc.  In terms of the cellular changes itself, the nature of genetic events associated with cancer progression has been the centre of attention for several decades. These fairly well defined genetic changes typically involve mutations and chromosomal changes such as rearrangements, duplications etc. Whilst, some of these genetic events are clearly both causal and necessary for tumour evolution, there is a spectrum of changes that occur that may be the consequence of the cancer. More importantly, from a therapeutic strategy, the success in targeting presumably well defined genetic events has met with some what limited success. Thus, we have been interested in exploring the role of signaling pathways that primarily regulate differentiation of tissues in both embryonic and adult life. The questions that we have addressed are centered around the following themes with regard to Notch signaling.

• Is Notch signaling activated during human cancer progression?
• What are the mechanisms that lead to the activation of the Notch pathway?
• What are the functional consequences of the activation of Notch signaling and is it critical to the viability of tumor cells?
• What are the biochemical effector consequences of activating Notch signaling and how are the signals integrated into other cellular signaling pathways that drive tumor progression?
• Is there a specific temporal roles for Notch signaling and how does this integrate into the paradigm of immortalization followed by the generation of more progressive invasive cancers and then subsequent metastasis?
• What is the nature of human tumor cellular heterogeneity and how does Notch signaling regulate the maintenance or generation of heterogeneity?