“I don’t like dogmas much”

Nicola Aceto is a cheerful person. When he talks about his research, he laughs often and clearly feels at home in his office, even though it’s still almost empty. At the moment there’s just a desk with two screens, a meeting table and an empty shelf. The room will fill up a little more, says the biochemist, who is currently moving from the University of Basel to ETH Zurich. For example, the shelf will soon feature drawings by his two children as well as postcards and congratulatory cards from colleagues. On the bare walls, the first thing he wants to do is hang two pictures of the discovery to which he owes his success: coloured microscope images of clusters of tumour cells. Metastases often grow from such clusters in cancer patients. The ETH Professor of Molecular Oncology has received numerous awards for his discovery of these cell clusters and their significance, including the recent Swiss Science Prize Latsis, which will be officially presented to him on 4 November of this year.

Knowledge from over a century ago

Aceto’s success story began in 2014. Back then, as a young postdoctoral fellow at Harvard Medical School in Boston, he examined blood samples from cancer patients and observed clumps of four or five connected tumour cells in them for the first time. He decided to investigate them further. Doing so was not the obvious choice, as many cancer researchers believed that metastases arise from individual circulating tumour cells (CTC). Such cells detach from the original or primary tumour and travel through the bloodstream to other parts of the body, where they sometimes take hold, divide and grow into metastases. With this already known, the cell clusters Aceto found were not necessary to explain metastasis formation. Nevertheless, rather than putting his discovery aside, he looked into it more closely.

First, he made sure that what he had observed wasn’t an isolated incident. Initial confirmation came from scientific publications more than 100 years old describing clumps of cells found in blood vessel sections. The authors called these “micro-emboli” and they suspected even then that their finding was related to the formation of cancer metastases. But such results couldn’t be refined for a long time because of the extreme dilution of cancer cells in the blood, as Aceto illustrates: “In 10 millilitres of patient blood, there are about 50 billion red blood cells and 50 million white blood cells floating around – but only a handful of tumour cells.” That’s why it wasn’t until the advent of microfluidic technologies, which can handle very small volumes of fluid and capture rare tumour cells with high precision, that researchers were able to efficiently detect and study cancer cells in blood samples.

Against the establishment

Using these methods, Aceto analysed blood samples from hundreds of cancer patients. He found that in sufferers who had such tumour cell clusters in their blood, the cancer progressed more rapidly than in patients with individual CTCs. In addition, in experiments with mice he showed that metastases grow 50 times more frequently from such cell clusters than from individual tumour cells.

Aceto thus upended the prevailing dogma that had viewed individual cancer cells as the seeds for metastases. However, publishing the results, which were surprising to the community, was difficult, and the review process was long and involved, Aceto recalls. But it wasn’t stressful for him, he says with a smile; on the contrary, he enjoyed it. Moreover, it was very challenging for reviewers to find fault with his data. It was eventually recognised and the work published in the prestigious journal Cell.

“We’d discovered something fundamentally new that may be of great importance for cancer patients,” Aceto says. That’s because most of them do not die from the primary tumour, but from metastases. Across all cancer types, such secondary tumours are responsible for nine out of ten deaths. “Cancer drugs to date have all been designed to destroy tumour cells,” Aceto says, which is one of the reasons why primary tumours can be successfully controlled in some cases. However, such therapies are often unable to destroy all a tumour’s cells. This means treatment sometimes exerts selective pressure, clearing a path for the most resistant cancer cells to resurge – sometimes years later – in the form of metastases.

A new way to treat cancer

With the discovery of tumour cell clusters, however, Aceto had now found a completely new way to combat the emergence of metastases. His idea is to use drugs to get the cell clusters to break down into individual cells and prevent metastases from forming. “Such a treatment could complement traditional cancer drugs,” he says.

To lay the groundwork for this kind of therapy, Aceto first investigated which molecular processes in the cell clusters lead to the formation of metastases. His team recognised that the cells in such a cluster differ from individual, circulating cancer cells in several important aspects: for instance, CTC cluster cells proliferate more actively and display features that have been previously associated to stem cells. “This makes it easier for these cells to implant themselves in another part of the body and form metastases.”, Aceto says. In addition, the cell clusters have a mechanical advantage: unlike single cells, the larger clumps tend to get stuck in the narrow capillaries. In such bottlenecks, they then set up home, as it were – and grow.

Unconventional

Further investigation by Aceto’s team revealed why cell clusters detach from the primary tumour in the first place: specifically, they leave areas of the tumour that are poorly supplied with oxygen by blood vessels. “This is where it gets unconventional,” Aceto says. The controversy stems from the fact that some cancer drugs precisely target the blood vessels with the aim of lowering the oxygen supply to the tumour in order to weaken it. According to Aceto’s results, however, such therapy could simultaneously promote the detachment of cell clusters and thus the formation of metastases.

Once again, Aceto came to a conclusion that cast doubt on current views, even on currently applied forms of therapy. During the review process to publish the findings, the verdict was that they were “too unconventional”. The paper has since been published in another journal than he intended.

Why does Aceto keep taking on such controversy? “I don’t like dogmas much,” he says. “They aren’t helpful, and can also cause you to overlook important things.” That he sometimes has to fight battles against prevailing misconceptions is something Aceto finds exciting. “I have the best job in the world,” he says. Although, the native Italian admits with a smile, he would have also liked to be a professional football player!

Getting started at ETH Zurich

Aceto plans to continue pursuing his approach at ETH. Since January 2021, the conversion of his laboratory on the Hönggerberg campus has been in full swing. One new feature is a closed laboratory area with strict hygiene and safety regulations, where patients’ blood samples will be tested in future. By early November, everything should be ready for Aceto’s research group to move in.

Incidentally, the researchers have already found an initial indication of a possible active agent to wield against the tumour cell clusters. They analysed over 2,400 approved drugs to see if these also had an effect on the clusters. What they found was a certain type of molecule that now helps people with cardiac arrhythmias, called Na+/K+-ATPase inhibitors. These separate the clusters into individual cells, presumably disarming them. The first clinical trial with breast cancer patients is currently underway.

In addition, Aceto says, a “super cool” new publication from his team is currently under review. He doesn’t want to reveal more details yet, but it’s a good bet that in it, he once again goes against an established opinion. No question: we can expect many surprises from Nicola Aceto in the future.