Cadherin cell-cell adhesion and tissue organisation in health and disease

The broad interest of the group is to understand how epithelial cells generate, and sense, mechanical force at the junctions that connect them with one another. We are exploring the hypothesis that this mechanotransduction allows epithelial cells to detect diverse changes in their neighbours. Thus, it is a mechanism to detect, and respond to, events that challenge epithelial integrity and homeostasis.

Epithelia are the principal tissue barriers of the body, and the sites for major diseases such cancer, infection and inflammation. We take a multidisciplinary approach to tackling this problem, working with experts in developmental biology, inflammation, cancer, mathematics and engineering across the world. Our projects aim to understand the fundamentals of mechanics and mechanotransduction at cell-cell adhesions; elucidate how these support epithelial homeostasis; and define how their dysfunction may contribute to cancer and inflammation.

1) Generating force at cell-cell junctions: signals, cytoskeleton and mechanics.

Here we are discovering how complex signaling networks control the cytoskeleton to generate mechanical force at junctions. We combine cell biology with high-resolution quantitative microscopy, novel tools to detect cell signals, and computational theory, using both cell cultures and zebrafish as our models.

2) Detecting forces at cell-cell junctions.

This project aims to identify the mechanisms that allow cells to detect change in force at the junctions with their neighbours. Ultimately, this is the fundamental basis of mechanotransduction. We have found many signaling pathways and identified elements of the adhesion and cytoskeleton systems as detectors of force.

3) Mechanotransduction and epithelial homeostasis.

Contractile cell-cell junctions constitute a network that links cells into epithelial tissues. We are testing the concept that local changes in contractility, that are signs of disturbed cells, can propagate in this network alerting neighbouring cells to the change. The fundamental basis for this lies in understanding how forces propagate in tissues, how fast and how far they can be detected.

4) Forces, junctions and cancer.

All cancers undergo transitions during their lifetime, when they exist as small numbers of transformed cells surrounded by a majority of untransformed cells. These minorities can be physically expelled from the epithelium, a potential protective mechanism that can limit tumor development. We are testing how mechanical signals allow untransformed cells to detect nearby transformed cells. Conversely, we seek to understand how mechanical signals from tumor cells can alter the behaviour of their normal neighbours, if the latter fail to remove the former.

5) Protecting epithelia from cell death.

Cell death is an inevitable part of life, even in healthy epithelia. However, mechanisms must exist to remove fatally-injured cells and maintain epithelial barriers. We have discovered that mechanotransduction allows epithelial cells to detected injured neighbours and remove them. We are working with experts in zebrafish models and inflammation to understand the place of mechanotransduction in protecting epithelial homeostasis from the challenge of cell injury.

6) Collective cell migration.

Epithelial cells move together when they need to shape tissues or repair wounds. But how they coordinate their migration is still poorly understood. We hypothesize that transmission of forces allows migrating cells to signal to one another, with the implication that abnormal mechanotransduction may disrupt cell migration in development and disease.

To discuss the group's projects further, contact Professor Alpha Yap

+61 7 334 62013
a.yap@imb.uq.edu.au

Post-doctoral position in epithelial mechanobiology available in the Yap Lab (Institute for Molecular Bioscience, University of Queensland).

There is an exciting opportunity for a post-doctoral researcher to join the ARC Laureate Program led by Professor Alpha Yap at the Institute for Molecular Bioscience, University of Queensland (Brisbane, Australia). The program’s overall goal is to understand how mechanical communication between cells supports the homeostasis and integrity of epithelial tissues. The team takes an interdisciplinary approach, working with national and international collaborators to combine experimental cell biology, optical microscopy, biophysical assays and physical theory. To complement this program, we are seeking an ambitious, creative scientist to lead work that analyses how tissue mechanics and mechanical signaling respond to homeostatic stresses, such as apoptosis, in epithelial tissues. Experimental models include zebrafish embryos and cellular systems. Candidates with research expertise in the zebrafish model are especially sought for this project.

This is a full-time position, being offered as a 3-year contract with the potential for renewal depending on performance and funding. It is an opportunity for a research scientist to expand their capacity, extend their professional research network, and develop leadership in research and supervision. 

Contact: Professor Alpha Yap

+61 7 334 62013
a.yap@imb.uq.edu.au

PhD Scholarships available in the Yap Lab (Institute for Molecular Bioscience, University of Queensland).

Topic: How epithelial tissues detect and respond to cell death and injury.

Project Description

Two PhD projects are available as part of Professor Yap’s ARC Laureate Program which commences in 2024. This prestigious 5-year program aims to understand how cells communicate with one another by mechanical force to detect injury in epithelial tissues such as the gastrointestinal tract and embryonic skin. We apply physical and cell biological approaches to understand how those mechanical forces are generated and detected for tissue health and repair. We use innovative approaches from different disciplines, including live-cell microscopy and genetic manipulation in zebrafish embryos; experimental tools and theory from physics that provide new ways to understand the biological phenomena; and testing how failure of mechanical communication may allow injury to disrupt tissue integrity. Individual projects will be designed that emphasize different aspects within this overall program, tailored for the specific interests of students, which can range from biology to biological physics. Independent of the specific focus of an individual project, the interdisciplinary range of this Laureate Program provides an exciting opportunity for students to train across biological and physical disciplines, to enhance their capacity and versatility for the future.

Research Environment

These projects will be supported by the world-class resources of the IMB and the network of national and international experts who are collaborating with Professor Yap’s ARC Laureate Program. Depending on the specific requirements of each project, students have the opportunity to learn cutting-edge experimental approaches, such as biophysical techniques to analyse tissue mechanics and the use of organoids and zebrafish embryos to model cell injury and tissue responses. This project is part of a program that provide a rich, interdisciplinary network for their training. Local collaborators bring experience in cell biology (Prof. Rob Parton, Dr. Samantha Stehbens), zebrafish models (Dr Anne Lagendijk),inflammation (Professors Kate Schroder and Matt Sweet) and gastrointestinal function (Professor Jake Begun, MMRI-UQ); while national and international collaborators bring expertise in mechanobiology (e.g. Richard Morris, UNSW; Virgile Viasnoff, Nat Uni Singapore; Phillipe Marcq, ESPCI Paris). More broadly, the IMB and UQ campus provide a vibrant, multidisciplinary environment for this training, where they will get exposure to disciplines such as developmental biology, gastroenterology and genomics, as well as the cell biology and biophysics of the host lab.

Contact: Professor Alpha Yap

+61 7 334 62013
a.yap@imb.uq.edu.au

Find out more about Research Training at IMB:

Study at IMB

• Journal Article: Mammalian diaphanous 1 mediates a pathway for E-cadherin to stabilize epithelial barriers through junctional contractility

  Acharya, Bipul R., Wu, Selwin K., Lieu, Zi Zhao, Parton, Robert G., Grill, Stephan W., Bershadsky, Alexander D., Gomez, Guillermo A. and Yap, Alpha S. (2017) Mammalian diaphanous 1 mediates a pathway for E-cadherin to stabilize epithelial barriers through junctional contractility. Cell Reports, 18 12: 2854-2867. doi:10.1016/j.celrep.2017.02.078

• Journal Article: Laser-mediated rupture of chlamydial inclusions triggers pathogen egress and host cell necrosis

  Kerr, Markus C., Gomez, Guillermo A., Ferguson, Charles, Tanzer, Maria C., Murphy, James M., Yap, Alpha S., Parton, Robert G., Huston, Wilhelmina M. and Teasdale, Rohan D. (2017) Laser-mediated rupture of chlamydial inclusions triggers pathogen egress and host cell necrosis. Nature Communications, 8 . doi:10.1038/ncomms14729

• Journal Article: Bistable front dynamics in a contractile medium: Travelling wave fronts and cortical advection define stable zones of RhoA signaling at epithelial adherens junctions

  Priya, Rashmi, Gomez, Guillermo A., Budnar, Srikanth, Acharya, Bipul R., Czirok, Andras, Yap, Alpha S. and Neufeld, Zoltan (2017) Bistable front dynamics in a contractile medium: Travelling wave fronts and cortical advection define stable zones of RhoA signaling at epithelial adherens junctions. Plos Computational Biology, 13 3: . doi:10.1371/journal.pcbi.1005411

View all Publications

We seek to make our expertise a resource for the larger community.

Reagents that we have developed have been widely applied to test cell signaling, adhesion and the cytoskeleton and our analytical protocols are freely distributed.

The scientific impact of our research program is also demonstrated by regular invitations to present our latest work at international and national conferences; public lectures (at venues such as The Royal Institution, London); and commentaries both in top scientific journals and the press.

We collaborate across several disciplines and countries. Long-standing collaborators include:

• Professor Robert Parton (Cell Biology, IMB)
• Associate Professor Ben Hogan (Developmental Biology, IMB)
• Dr Guillermo Gomez (Signaling and Biophysics, Uni SA)
• Dr Zoltan Neufeld (Mathematical modelling, UQ)
• Associate Professor Kate Schroder (Inflammation and immunity, IMB)
• Professor Benoit Ladoux (Institut Jacques Monod, Paris)
• Associate Professor Virgile Viasnoff (Biophysics, National University of Singapore and CNRS, France).