Project Title: Tumours Fuelled by the Squeeze - can Hippo Release the Pressure?

The Hippo pathway is a kinase cascade that acts as an intermediary signalling pathway relaying upstream signals, such as cell-to-cell contact [1], G protein-coupled receptor signals [2] and mechanotransduction signals [3]. Transcriptional co-activators Yes-associated Protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the primary downstream targets of the Hippo pathway, which associate with TEAD transcription factors to promote expression of genes that promote cell proliferation and stemness [4,5]. Of the upstream regulators, mechanotransduction has been implicated to be an important factor in determining transcriptional activity of YAP/TAZ [6,7].

Elevated pressure in tumours contributes to poor prognosis while promoting tumour growth and increasing metastatic potential [8]. Moreover, increased interstitial fluid pressure within tumours has also been suggested to impede delivery of anticancer drugs to the tumour and thus reduce response to therapies [9]. As YAP/TAZ are activated by cellular mechanical stress and stiffening of the matrix [3,10], transcriptional output of YAP/TAZ may be altered under these conditions that may be involved in promoting cancer progression.

Through the use of genome editing techniques (e.g. CRISPR/Cas9), digital holographic microscope (DHM), Hi-C and transcriptional analysis, the overall aim of the project is to investigate the role of elevated interstitial pressure on transcriptional output mediated by YAP/TAZ and how this regulates cancer cell proliferation, cell survival and response to chemotherapy. The first part of the project will focus on osteosarcoma and based on preliminary data from Gram Hansen Lab, it is hypothesised that elevated hydrostatic pressure will activate YAP/TAZ, promote expression of YAP/TAZ target genes and cell proliferation in osteosarcomas.

References
[1] Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue T, Yu J, Li L, Zheng P. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & development. 2007; 21(21):2747-61.
[2] Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH, Zhao J, Yuan H, Tumaneng K, Li H, Fu XD. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell. 2012;150(4):780-91.
[3] Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, Elvassore N. Role of YAP/TAZ in mechanotransduction. Nature. 2011; 474(7350):179-83.
[4] Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, Chinnaiyan AM, Lai ZC. TEAD mediates YAP-dependent gene induction and growth control. Genes & development. 2008; 22(14):1962-71.
[5] Zhao B, Kim J, Ye X, Lai ZC, Guan KL. Both TEAD-binding and WW domains are required for the growth stimulation and oncogenic transformation activity of yes-associated protein. Cancer research. 2009; 69(3):1089-98
[6] Dupont S. Role of YAP/TAZ in cell-matrix adhesion-mediated signalling and mechanotransduction. Experimental cell research. 2016 Apr 10;343(1):42-53.
[7] Panciera T, Azzolin L, Cordenonsi M, Piccolo S. Mechanobiology of YAP and TAZ in physiology and disease. Nature reviews. Molecular cell biology. 2017 Sep 27.
[8] Ariffin AB, Forde PF, Jahangeer S, Soden DM, Hinchion J. Releasing pressure in tumors: what do we know so far and where do we go from here? A review. Cancer research. 2014 May 15;74(10):2655-62.
[9] Heldin CH, Rubin K, Pietras K, Östman A. High interstitial fluid pressure--an obstacle in cancer therapy. Nature reviews. Cancer. 2004 Oct 1;4(10):806.
[10] Aragona M, Panciera T, Manfrin A, Giulitti S, Michielin F, Elvassore N, Dupont S, Piccolo S. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell. 2013 Aug 29;154(5):1047-59.