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

The silent language of epithelial cells, and how deciphering it could explain cancer.

Our epithelial cells are our first line of defence. They form the tissue barriers of our bodies – a wall between the inside and the external environment. These cells are like warriors in an army. They work as a system, coordinating their behaviour, communicating amongst themselves to protect us from harm. In the process of warding off germs and toxic substances, cells become damaged. When they do, the other cells in the system eradicate the cell and continue their duty.

But sometimes the system breaks down. Diseases like breast cancer, colon cancer, prostate cancer, and lung cancer are the result. In fact, the vast majority of solid tumours occur in epithelial tissues. How do these cells communicate? What are all the parts of the system? What are the critical functions that can’t be allowed to malfunction? And what happens when they do fail?

Cell biologist Professor Alpha Yap is leading a team of scientists to describe the epithelial system and learn the silent language of these microscopic warriors.

A potential cancer cell extruding from an epithelium. Image credit: Selwin Wu, Yap Lab

Research overview

“In the epithelial system, billions and billions of cells coordinate their behaviour to make barriers. Understanding the critical mechanisms that allow them to do their job will help us to understand how and why their jobs fail," said Professor Yap.

Professor Yap's team believe that cells communicate amongst themselves through mechanical force, as if they were constantly shaking hands with one another. Changes in force are then detected to alert them to a problem. Exploring this as a communication method within the body is an emerging field of science called mechanobiology.

Professor Yap’s team is at the leading edge of mechanobiology, which has the potential to explain important aspects of cancer.

"You could live with cancer in your body if it stayed where it started. The problem is when it starts to spread. At least in part, the spread is happening because of defective cell communication."

Research projects

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

Research training opportunities

Research title: Cadherin signalling and morphogenesis

Summary of research interests: My group studies the morphogenetic mechanisms of cadherin adhesion molecules. These cell surface receptors are key determinants of tissue patterning during development and wound healing. Importantly, cadherin dysfunction is a major factor in common human diseases, such as tumour invasion and epithelial inflammation. We believe that understanding the cell and molecular mechanisms by which cadherins control normal tissue patterning will provide valuable insights into how cadherin dysfunction contributes to disease. A major focus of our work lies in understanding how cadherin signalling regulates the cytoskeleton, and the morphogenetic impact of these processes, especially through control of contractile forces at cell-cell junctions. We craft potential projects to the interests of students, guided by the momentum of projects that are established in the laboratory.

Traineeships, honours and PhD projects include

  • Control of tissue tension by cadherin-cytoskeletal interactions
  • Cell-cell junctions and cell migration
  • Dynamic cytoskeletal organisation at cadherin junctions: its regulation in health and disease
  • Regulation and dysregulation of junctional mechanics: impact for epithelial organisation and tumour invasion.

Contact: Professor Alpha Yap

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


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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.

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Professor Alpha Yap

Group Leader, Cell Biology and Molecular Medicine Division

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


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