Tissue size control and the regulation of Hippo pathway activity in mammals

How tissues stop growing upon reaching their correct size is a mystery in biology. The barriers that tissues encounter when they reach their final size may bear relevance to neoplastic cells during the early stages of tumorigenesis. Drosophila genetics increased our understanding of the biology of organ size control. The Hippo pathway has emerged as a key pathway that controls tissue expansion through the regulation of cell proliferation and death. Interestingly, all components of the Hippo pathway are conserved in mammals and some have been implicated in cancer. Conceptually, mechanisms that control tissue size may interact at different levels with wound healing or regeneration signalling cascades. Likewise, processes controlling the number and activity of tissue stem cell pools may possibly engage tissue size control pathways. In this context, many critical questions remain unanswered: how is the Hippo pathway turned on and off; which precise signals are pathway inputs; how does the pathway cross-talk with other signalling pathways; and how are such signalling schemes deregulated during tumorigenesis? We propose to use a combination of biochemical and genetic experiments to gain a detailed understanding of Hippo pathway regulation in mammals. We have generated mouse models to address the extent to which regulatory mechanisms observed in Drosophila can be translated to mammals. We plan to use biochemical approaches to identify mammalian proteins that associate with Hippo pathway components. Using accurate and sensitive readouts for Hippo pathway activity, we will conduct genetic screens to identify new components of the pathway. Mutations in components of the Hippo pathway have been identified in human tumours and abnormal Hippo pathway activity is observed in an even larger fraction of cancers. Therefore, we foresee that this multi-disciplinary approach to identify the activating and inactivating signals in this canonical cascade may suggest new therapeutic strategies to combat cancer.