“Cancer cells don’t invent new functions. For example, the ability of cancer cells to rapidly multiply is also a typical characteristic during the developmental stage, when the embryo grows from a single cell to billions of cells over a short period,” says Claudio Cantù, professor of cell and molecular biology at Linköping University, who led the study published in the journal PNAS.
He is a researcher in developmental biology and has for several years studied one of the most important signalling pathways during embryo development: Wnt signalling. Wnt is a molecule that cells can secrete to communicate with another cell, which then changes its behaviour – often by forming new cells faster. Wnt plays a critical role during this period of cell life. If the signalling is switched off, the organism stops developing.
But Wnt signalling also has a role in cancer, and that is a negative one. Around 8 in 10 cases of colorectal cancer occur because the cell loses control of the Wnt signalling pathway. When Wnt activity is too high, the cell divides uncontrollably.
Unfortunately, it is extremely difficult to turn off Wnt signalling in the body with therapeutics because the same molecule also has an indispensable role in the body’s regulation of normal cell growth. Some types of cells, such as red blood cells and intestinal cells, are constantly made and replaced. The old cells that die must be replaced by stem cells forming the right amount of new cells.
“Wnt is overactive in colon and rectal cancer, so if we could block Wnt, the cancer would theoretically be cured. But, at the same time, the treatment would kill stem cells in the intestine and the person would die even faster than they would have done with the tumour. So, is it possible to block the Wnt signal without doing harm?” asks Claudio Cantù.
Yes, maybe. The researchers behind the study have added an important piece to this puzzle. During embryo development, Wnt cooperates with a protein called TBX3, which controls the development of the legs, arms and heart. In other words, if the TBX3 gene is damaged by mutations, it leads to defects in various organs, such as the heart and limbs. Claudio Cantùs’s research group has previously discovered that this cooperation between Wnt and TBX3, somewhat surprisingly, also occurs in cancer cells in the large intestine.
“It’s a universal mechanism and for me there’s an inherent beauty in discovering how it works. For example, TBX3 controls the formation of the limbs of humans and all other vertebrates, and it controlled the same processes in the dinosaurs. But it’s also important to understand this mechanism, because in this study we found that TBX3 activates genes that make colorectal cancer more prone to spread,” says Claudio Cantù.
The researchers show that various molecular interactions are necessary for TBX3’s ability to make cancer cells more likely to form secondary tumours, or metastases, that spread throughout the body. The discovery opens up opportunities to develop therapeutics that target these interactions and prevent tumour cells from spreading.
“Our new findings also indicate that TBX3 is important for the cancer cell, but not for normal stem cells in the intestine. The discovery means that it may be possible to inhibit TBX3 in cancer cells without harming the patient,” says Claudio Cantù.
The research project is an international collaboration between researchers in Sweden, Japan, Russia and Switzerland. The research has been funded with support from, among others, the Swedish Cancer Society, the Swedish Research Council, Additional Ventures (USA), the Joanna Cocozza Foundation for Children’s Medical Research, the Knut and Alice Wallenberg Foundation, the Japan Society for the Promotion of Science (JSPS) in Japan and the Swedish Foundation for International Cooperation in Research and Higher Education (STINT).
Article: The Developmental Factor TBX3 Engages with the Wnt/β-catenin Transcriptional Complex in Colorectal Cancer to Regulate Metastasis Genes, Amaia Jauregi-Miguel, Simon Söderholm, Tamina Weiss et al., (2025), Proceedings of the National Academy of Sciences (PNAS), published online 9 May 2025, doi: https://doi.org/10.1073/pnas.2419691122