Hippo-YAP/TAZ signalling in stem cells, regeneration and cancer

Most human cancers arise in epithelial tissues, such as the skin or intestinal tract.  A population of basal stem cells normally proliferates to maintain epithelial homeostasis and to regenerate tissues after damage.  The same stem cells are also the origin of tumour formation.   We seek to understand how epithelial stem cells normally function and how their activity becomes mis-regulated in cancers.  

My laboratory uses Drosophila, mouse and human organoids in culture as model systems to explore how stem cells construct epithelial tissues during development and how epithelial tumours can arise.

We focus on the questions of how cell polarity organises the behaviour of cells within an epithelium, and how signalling pathways control cell proliferation within an epithelia.  A major interest has been the Hippo-YAP/TAZ signalling pathway, which responds to apical and basal polarity cues, cell-matrix interactions, and mechanical forces to regulate cell proliferation and cellular morphology during development.

Our experiments combine three main approaches to identify molecular mechanisms responsible for organising cell polarity and cell behaviour during tissue growth and morphogenesis in epithelia:

  • Genetic analysis of gene functions in vivo;
  • Live-imaging of epithelial tissue development; and
  • Organoids and tumour cells in culture
  • Mouse models of tumour growth and metastasis
  • Analysis of human cancer patient samples
Intestinal organoid
Hippo signalling
  • Genetic analysis of gene functions in vivo;
  • Live-imaging of epithelial tissue development; and
  • Computational modelling of cell polarity and cell behaviour.
  • Mechanisms of signal transduction via the Hippo-YAP/TAZ pathway
  • Regulation of Hippo-YAP/TAZ by epithelial polarity, cell adhesion, extracellular matrix and tissue damage
  • Role of YAP/TAZ in tissue development, stem cells and regeneration
    ·       YAP/TAZ as a driver of squamous cell carcinoma progression to metastasis
    ·       YAP/TAZ as a driver of colorectal cancer progression to metastasis
Drosophila egg chamber
Drosophila tumour
Authors
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Ahmed Elbediwy, Yixiao Zhang, Mathias Cobbaut, Philippe Riou, Ray S Tan, Selene K Roberts, Chris Tynan, Roger George, Svend Kjaer, Marisa L Martin-Fernandez, Barry J Thompson, Neil Q McDonald, Peter J Parker

J Cell Sci jcs. 223743. (2019)

Mario Aguilar-Aragon, Georgina Fletcher, Barry James Thompson

bioRxiv 592311 (2019).

Clara Sidor, Nerea Borreguero-Munoz, Georgina Fletcher, Ahmed Elbediwy, Hannah Vanyai, Oriane Guillermin, Barry J Thompson

BioRxiv 595439. (2019)

Thompson BJ

The EMBO journal 37 (23) (2018).

Oliver Gordon, Conor M Henry, Naren Srinivasan, Susan Ahrens, Anna Franz, Safia Deddouche, Probir Chakravarty, David Phillips, Roger George, Svend Kjaer, David Frith, Ambrosius P Snijders, Rita S Valente, Carolina J Simoes da Silva, Luis Teixeira, Barry Thompson, Marc S Dionne, Will Wood, Caetano Reis e Sousa

eLife, 7, e38636. (2018)

Zoe Vincent-Mistiaen, Ahmed Elbediwy, Hannah Vanyai, Jennifer Cotton, Gordon Stamp, Emma Nye, Bradley Spencer-Dene, Gareth J Thomas, Junhao Mao, Barry Thompson. 

eLife 7, e33304. (2018)

Robert P Ray, Poulami S Ganguly, Silvanus Alt, John R Davis, Andreas Hoppe, Nic Tapon, Guillaume Salbreux, Barry J Thompson

Developmental Cell 46 (1), 23-39. (2018)

BJ Thompson, FG Giancotti

Current opinion in Cell Biology 51, iv-vii. (2018)

Mario Aguilar-Aragon, Ahmed Elbediwy, Valentina Foglizzo, Georgina C Fletcher, Vivian SW Li, Barry J Thompson

Cell reports 22 (7), 1639-1646. (2018)

A Elbediwy, BJ Thompson

Current opinion in cell biology 51, 117-123/. (2018)

Fletcher, G.C., Diaz-de-la-Loza, M.D., Borreguero-Munoz, N., Holder, M., Aguilar-Aragon, M., and Thompson, B.J. (2018)

Mechanical strain regulates the Hippo pathway in Drosophila.

Development. 145(5).

Elbediwy, A., Vincent-Mistiaen, Z.I., Spencer-Dene, B., Stone, R.K., Boeing, S., Wculek, S.K., Cordero, J., Tan, E.H., Ridgway, R., Brunton, V.G., et al and Thompson, B.J. (2016)

Integrin signalling regulates YAP and TAZ to control skin homeostasis.

Development. 143: 1674-1687.

Fletcher, G.C., Elbediwy, A., Khanal, I., Ribeiro, P.S., Tapon, N., and Thompson, B.J. (2015)

The Spectrin cytoskeleton regulates the Hippo signalling pathway.

EMBO J. 34: 940-954.

Thompson BJ, Cohen SM. (2006)

The Hippo pathway regulates the bantam microRNA to control cell proliferation and apoptosis in Drosophila.

Cell. 126(4): 767-74.