1 April 2021

'Live' measurements of cell signals show need for combination therapy in colorectal cancer

The team of Oncode Investigator Hugo Snippert (UMC Utrecht) has succeeded in using organoid technology to monitor live how a colon tumor responds to a combination therapy. The results appear today, April 1st, in the leading journal Nature Cell Biology. His work offers many leads for follow-up research and that is still needed: colorectal cancer kills more than 4,800 people in the Netherlands each year.

Peter Thijssen Support Staff

Smart combination

Treating colorectal tumors with the common mutations in the KRAS/BRAF genes requires a combination of different drugs. Almost ten years ago, Oncode Investigator Rene Bernards (NKI) showed for the first time that inhibiting multiple components of cellular signaling pathways is necessary for effective treatment of this type of tumor. However, until now it was still unclear at the molecular level why this combination therapy is necessary. With organoid technology developed in the lab of Oncode Investigator Hans Clevers (Hubrecht Institute), mini-tumors have been grown from patient material in which the effect of drugs on the behavior of tumor cells can be measured using new methods. This has made it possible to very precisely measure the activity of the signaling pathways by which the cells communicate with each other.

"We knew that these types of tumors mainly respond to a combination of drugs, but not exactly why," Hugo explains. "With our Oncode base funding, we were able to invest in developing a very sensitive and precise measurement system: a microscopic technique that allows us to zoom in on individual cells and also to film over time how well these cells respond to treatments." Using the mini-tumors, the team shows in their paper that inhibiting signaling pathways in cells did not happen with a single therapy, but required a combination. "This is because we need to dampen these signaling pathways much harder than thought, and then we could measure before. Thanks to our precise measurement method, we now understand that there is a self-reinforcing mechanism in the signaling pathway and that you therefore have to push more than one button to sufficiently inhibit the sometimes complex signaling pathways to fight the tumor," explains Bas Ponsioen, post-doctoral researcher in the lab of Hugo and the leading author of the paper.

A microscopic photo of mini-colorectal tumours (left, courtesy of Joris Hageman), a heatmap image of signaling activity in individual cells (middle) and a quantification of the effect of combination treatment over time for individual cells (right).

Building on years of expertise

The work of Hugo Snippert and his team shows that our way of funding science and promoting collaboration works. "The best research happens in freedom. With Oncode's base funding, it was possible to conduct such high risk/high gain research. Science is also teamwork," Hugo adds. "Our research builds on the insights of Oncode colleagues such as Rene Bernards, Hans Bos and Hans Clevers." Hugo is an example of the new generation of researchers who can build on the high level of cancer research in the Netherlands in the years to come. "These results offer my lab many new opportunities. With this system, in collaboration with various partners, we can find out which cells don't respond to treatments at all, why they don't, and whether alternative treatment combinations would be effective."

Ultimately, these steps lie at the heart of better treatments for colorectal cancer, a disease that kills more than 4,800 people in the Netherlands each year.

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