In the Harvey laboratory, we study mechanisms that control organ size during development and how deregulation of these processes contributes to human cancer.
More specifically, we:
- Investigate developmental organ size control in the vinegar fly Drosophila.
- Characterise the function of the Hippo pathway in Drosophila.
- Investigate the role of the Hippo pathway in human cancer.
Control of organ size by the Hippo pathway
Organ size control is a fundamental but poorly understood aspect of life. A key signalling network that controls organ size is the Hippo pathway. To investigate how this pathway regulates organ size, we are monitoring pathway activity in real time in Drosophila organs, which we culture ex vivo. We use advanced microscopic techniques and a number of endogenously tagged Hippo pathway genes that we have generated using CRISPR-Cas9 genome editing. These studies will reveal new insights into Hippo signalling in the context of organ size control.
Searching for the complete Hippo pathway
By using the vinegar fly Drosophila, we played an important role in the discovery and characterisation of the Hippo pathway, which is now known to be an evolutionarily conserved regulator of organ size. We have identified 15 Hippo pathway proteins, including the founding members of the core kinase cassette and the first transmembrane receptor protein, the cadherin Fat. Using large-scale proteomics and in vivo genetic screens, we have discovered many novel Hippo pathway proteins and are currently investigating their mechanism of action.
The Hippo pathway and cancer
The Hippo pathway is frequently deregulated in many human cancers, including lung, colorectal, breast and ovarian cancer and melanoma. We have a specific interest in two cancers: melanoma and mesothelioma. Using patient samples, cancer cell lines and high-throughput functional genomics, we are investigating the role of the Hippo pathway in these diseases. Our studies are enhanced by collaborations with clinician researchers who have expertise in these diseases, such as Dr Mark Shackleton. Furthermore, by applying our knowledge of Hippo signalling, we are searching for novel treatments for these diseases.
Manning SA, Dent LG, Kondo S, Zhao ZW, Plachta N, Harvey KF (2018). Dynamic Fluctuations in Subcellular Localization of the Hippo Pathway Effector Yorkie In Vivo.
Curr Biol. 28(10):1651-1660.
Poon CL, Mitchell KA, Kondo S, Cheng LY, Harvey KF (2016). The Hippo Pathway Regulates Neuroblasts and Brain Size in Drosophila melanogaster. Curr Biol. 26(8):1034-42.
Harvey KF, Zhang X and Thomas DM (2013). The Hippo pathway and human cancer. Nat Rev Cancer. 13(4):246-57.
Poon CLC, Lin JI, Zhang X and Harvey KF (2011). The sterile 20-like kinase Tao-1 controls tissue growth by regulating the Salvador-Warts-Hippo pathway. Dev Cell. 21(5):896-906.
Zhang X, George J, Deb S, Degoutin JL, Takano EA, Fox SB, AOCS Study Group, Bowtell DDL and Harvey KF (2011). The Hippo pathway transcriptional co-activator, YAP, is an ovarian cancer oncogene. Oncogene. 30(25):2810-22.
Bennett FC and Harvey KF (2006). Fat Cadherin Modulates Organ Size in Drosophila via the Salvador/Warts/Hippo Signaling Pathway. Curr Biol. 16(21):2101-10.
Harvey KF, Pfleger CM and Hariharan IK (2003). The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell. 114(4):457-67.