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We already know a lot about cancer. But the detailed process by which the first tumour cell develops into an aggressive cancer that can metastasise remains elusive. Researchers Jacco van Rheenen and Hugo Snippert are monitoring the development of cancer at the individual cell level. Their research will provide new insights that may well prove to be vital in the search for new strategies to fight cancer.

A video played on the laptop screen shows a small fragment of green-coloured breast cancer cells, of which a number detaches themselves from the bulk. “You can see how these cells metastasise,” says Jacco van Rheenen, group leader at the Hubrecht Institute. “We can give the cells different colours and follow them individually with a microscope.”

The imaging of individual cells is Van Rheenen’s speciality. In this new research project he is working with Hugo Snippert, a molecular cancer researcher at the UMC Utrecht. Snippert is conducting research into the behaviour of cancer (stem) cells using human mini-organs (known as organoids). The technology to culture organoids is an invention by Snippert’s former mentor Hans Clevers, who obtains much acclaims for this technology. Together, Snippert and Van Rheenen will make an in-depth study of cancer from its earliest stages.

Re-creating true physiology
“It all starts with a DNA defect,” Van Rheenen explains. “This may lead to a cell dividing in an uncontrolled manner. It is not yet a cancer, but only a benign tumour that is not harmful yet. It only becomes dangerous if a second or third defect occurs in the DNA. As a result, control mechanisms in the cell become disrupted and additional DNA defects can then easily accumulate. This will result in a cluster of cells with many different defects and fast proliferation. Once tumour cells are able to metastasise, we speak of malignant cancer. ”

“Up till now, cancer is studied by models in which tumours are created by simultaneously activating all DNA defects that will cause cancer,” Snippert continues. “This does not really reflect the natural process, because it neglects the gradual development of the tumour. We therefore want to replicate the stepwise accumulation of mutations that is reminiscent of actual human cancer biology.

We are using a technique that, assisted by laser light, creates a specific defect in the DNA of only one individual cell that we select during the microscopy. The selected cell may be the very first tumour cell, but we can also select a cancer cell that can form an aggressive cluster of cells in a pre-existing benign tumour. Subsequently, we can use the microscope to closely monitor the behaviour of those cells, for example their movements or proliferation. This has not been done before.”

New types of medication
The scientists hope that this method will reveal how cancer arises, evolves, and subsequently metastasises. “We may see tumour behaviour that we were not able to visualise before. New insights into cancer biology can result in better strategies to fight cancer and hopefully in the long term, to the development of different types of medication,” says van Rheenen. “Thanks to this research, we can also study how effectively chemotherapy attacks tumours cells with different DNA defects.”

The pair feels very much at home in Utrecht. “Fundamental research is carried out at the Hubrecht, which has many overlaps with the research that is performed at UMC Utrecht,” Snippert explains. “Utrecht is relatively small,” adds Van Rheenen, “but the research groups here are of international esteem with high collaborative synergy. We have a broad range of disciplines here, and it is precisely at those interfaces where very exciting things happen!”

Text: Roy Keeris