Wnt signalling interpreted differently depending on the receiving cell and signal duration

The same message can be interpreted differently by different individuals – also among cells. This is shown in a study by researchers at Linköping University who studied cell communication through Wnt signalling, which plays a decisive role in embryo development and cancer. Their findings, published in Cell Systems, are surprising in light of the prevailing conception of how Wnt signalling works.

The cells in our body are in constant communication. Although cell communication plays a decisive role in everything that happens in our bodies, cells have few ways to communicate with one another. Wnt signalling is one of them. It was discovered in the 1980s, through its role in the development of certain forms of cancer.

It soon turned out that Wnt signalling also has a basic function in embryo development in a variety of organisms, from fruit flies to humans.

“At the outset of life, Wnt signalling is vital for the body to form properly, while dysregulated communication between cells may lead to cancer. A key question we are trying to answer is whether this communication mode works in a similar way in these two distinct phases,” says Pierfrancesco Pagella, postdoc in the Department of Biomedical and Clinical Sciences at Linköping University.

It has long been known that when a cell sends a Wnt message to another cell, the receiving cell undergoes behavioural changes. This is achieved by activating certain genes in the genome and repressing others. Wnt signalling has long been regarded to always activate the same groups of genes, leading to the term “Wnt target genes”. But the current study upends this assumption, as the research group, led by Claudio Cantù, has shown that a signal may have radically different effects depending on its duration. In their experiments, the researchers saw that the same signal given to a specific cell type, such as embryonic stem cells, had significantly varying effects depending on the duration of the signal.

“The cell responds differently depending on whether the signal is delivered for 90 minutes, four hours or three days. It’s not simply a matter of prolonging the same message,” says Pierfrancesco Pagella.

A long-standing key issue in developmental biology is: as all cells contain the same genome, how does a cell know which of all the genome’s instructions to use to get its correct identity?

“I believe this discovery has uncovered a new type of cell behaviour related to the “instruction manual” of the genome. Some cells genuinely read and utilise the information to change their identity, while others choose not to use it for that purpose. Our study reveals how this works in the context of the Wnt signalling communication mechanism. This novel phenomenon, to our knowledge, has never been previously discovered,” says Claudio Cantù, senior associate professor.

What the researchers also discovered is that it has to do not only with the message, but also with the identity of the receiving cell. When the exact same signal is given to two different cell types, their immediate responses are also distinct. The researchers liken this to interpersonal communication, where the same message can be interpreted differently by different individuals.

The researchers believe that the reason behind this phenomenon is the cells’ prior experiences. One of the cell types subjected to Wnt signalling is immature embryonic stem cells. These are the youngest cells, and can be further developed into all the various specialised cell types in an organism. When the stem cells in the researchers’ experiment received Wnt signalling, their identity changed to resemble a specialised cell type, a behaviour that the researchers refer to as “plastic”.

The research team also studied how specialised cell types react to the same signalling. Despite receiving the same signal, these cells changed only temporarily, and ultimately returned to their initial state, an unexpected behaviour that the team at Linköping University call “elastic”.

One hypothesis that the researchers raise is that this second type of behaviour, “elastic”, may contribute to cancer cell aggressive behaviour. The new insights into this phenomenon may come to be used in the development of new treatment strategies to impact cancer cell response to Wnt signalling. This knowledge may also lay the foundation for discoveries of exactly which genes the signal targets in different situations.

The study was funded by the Swedish Cancer Society, the Knut and Alice Wallenberg Foundation at the Wallenberg Center for Molecular Medicine in Linköping, and the Swedish Research Council.

The article: The time-resolved genomic impact of Wnt/β-catenin signaling, Pierfrancesco Pagella, Simon Söderholm, Anna Nordin, Gianluca Zambanini, Valeria Ghezzi, Amaia Jauregi-Miguel and Claudio Cantù, (2023), Cell Systems, published online 19 July 2023, doi: https://doi.org/10.1016/j.cels.2023.06.004