In 2024, malignant tumors caused more than 21,300 deaths in Austria, 4.7% more than in 2014. Faced with a similarly pressing global challenge, scientists are striving to better understand what drives cancer cells to grow, spread, and invade healthy tissue. In Science Advances , a team at the Institute of Science and Technology Austria (ISTA) now offers new clues: Using a simplified model, the researchers show how a chaotic environment around tumor cells can promote their invasive behavior. This theoretical concept will need to be examined further in real tumor tissue.
Tumors arise from cells that multiply in their tissue of origin and form a collective. While some cells remain there, others invade neighboring tissues, spread throughout the body and ultimately metastasize to the lungs or liver, for example. To do so, individual cells detach from the collective—a process that was thought to be mainly determined by genetic factors. However, in recent years, the non-malignant microenvironment surrounding cancer cells has emerged as another possible driver of malignancy.
An interdisciplinary research team consisting of experimental biologists and theoretical physicists from ISTA’s Sixt and Hannezo groups , as well as the Francis Crick Institute, now shows how a disordered environment can trigger very specific behavior in spreading tumor cells.
Cancer cells and their microenvironment
“In the first phase of tumor spread, cells detach from the collective,” explains ISTA Professor Michael Sixt. “This is a hallmark of cancer. As individual cells, they can invade neighboring tissues much more efficiently. If they remained within the cell collective, they would not get very far and would stay in the tissue where they originated.”
There are several reasons why some tumor cells detach. One is genetic heterogeneity—the genetic diversity that drives tumor evolution. This is a long-established paradigm: variation is required, and certain variants are selected.
At the same time, there is growing research on the environment surrounding tumor cells. This concerns the interaction between cancer cells and their microenvironment, including stroma cells, blood vessels, immune cells, connective tissue, and signaling molecules, and how these factors can promote malignant progression.
“Some studies have shown that greater heterogeneity in the tumor environment can be a marker of higher malignancy,” Sixt continues. “So we asked ourselves: What does heterogeneity in the environment of tumor cells mean? How can we investigate it in the simplest possible model?”
Laboratory chips with a forest of pillars
Together with ISTA alum and co-first author of the study, Saren Tasciyan, the team decided to analyze the geometry of the environment. The experiment was designed so that everything remained constant except for the geometry through which the cells moved.
The researchers used so-called microfluidic chips: small laboratory devices in which tiny amounts of liquid flow through narrow channels. They are like Petri dishes in that they can be used to cultivate tumor cells, but they allow the scientists to control the cells’ physical environment much more precisely.
Tasciyan designed the chips with a forest of pillars through which the tumor cells had to move—similar to a microscopic obstacle course. First, the pillars were arranged as evenly and homogeneously as possible; then they were arranged in an irregular, heterogeneous pattern. Comparing the two conditions, the researchers observed that the tumor cell collective broke apart more readily in the heterogeneous geometry, with more individual cells detaching.
Collective memory
To find out why this happened, the Sixt group turned to their colleagues from ISTA Professor Edouard Hannezo’s research group, who specialize in physical principles in biological systems.
ISTA alum and co-first author Zuzana Dunajová used computer simulations incorporating basic cell properties, including their ability to self-propel and to adhere to other cells and their environment. In the simulations, cells likewise moved through ordered and disordered surroundings. The results closely mirrored the experimental observations.
“Although we didn’t understand these simulations at first, they are still much less complex than biology, so we thought we could use them as testing grounds for possible mechanisms,” Hannezo explains.
The analyses eventually made it clear that the cells do not respond only to their immediate surroundings at the moment they detach from a collective. They also have a history: they may already have passed through several constrictions or obstacles.
“That was the crucial point,” Hannezo continues. “In a disordered environment, a cell does not simply encounter disorder at one moment. It has already moved repeatedly through chaotic regions. As a result, the entire boundary of the cell collective changes—it becomes much rougher and develops significantly more finger-like protrusions.”
In summary, a cell collective exposed to a highly heterogeneous environment over an extended period becomes increasingly prone to breaking apart. It is effectively prepared—or “primed.” Once a critical threshold is reached, even small weak points can cause cells to detach from the tissue collective.
From a physics perspective, the findings point to an even broader principle. The behavior of the tumor cell invasion front can be described using the mathematical framework that also applies to seemingly unrelated physical systems. This reflects a concept known as universality : complex systems can display the same underlying patterns across different scales and materials. Examples include the spreading edge of a coffee stain or a forest fire.
A theoretical concept for cancer researchers and physicists alike
For the Sixt and Hannezo groups, the motivation was to make a fundamental conceptual idea visible: how tumor cells behave in relation to their environment. Their work bridges cancer biology and physics, reflecting ISTA’s core commitment to interdisciplinary research.
Alongside genetic and epigenetic factors, the study once again highlights the importance of a tumor’s microenvironment. None of these elements, however, should be viewed in isolation: they constantly interact with one another and together influence how malignant a tumor becomes.
“It was important to us to formulate and publish this concept in the hope that other researchers with more specialized expertise will take it up,” say the two ISTA professors. “The next step is for scientists to follow this approach into real tumor tissue and test it there.”
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Publication:
Dunajová & Tasciyan et al. 2026. Substrate heterogeneity promotes cancer cell dissemination through interface roughening . Science Advances . DOI: 10.1126/sciadv.aed0587
Science Advances
Computational simulation/modeling
Cells
Substrate heterogeneity promotes cancer cell dissemination through interface roughening.
9-Sep-2026