Chaotic tumor environments prime cancer cells for invasion, study shows

Cancer kills. In Austria alone, malignant tumors claimed more than 21,300 lives in 2024—a 4.7 percent increase from a decade earlier. The machinery of that death remains incompletely understood, which is why researchers at the Institute of Science and Technology Austria have begun asking a deceptively simple question: What makes a cancer cell decide to leave home?

For years, the answer seemed genetic. Tumors arise when cells in a tissue begin multiplying uncontrollably, forming a collective mass. Some cells stay put. Others break away, invade neighboring tissue, and eventually metastasize to distant organs like the lungs or liver. Scientists attributed this detachment primarily to genetic variation—certain mutations confer the ability to spread, and natural selection favors those variants. But in recent years, a parallel line of inquiry has emerged: the environment surrounding the tumor cells themselves may be just as consequential as the genes they carry. That microenvironment includes stromal cells, blood vessels, immune cells, connective tissue, and signaling molecules—a complex ecosystem that can either restrain or accelerate malignant progression.

A team led by Michael Sixt and Edouard Hannezo at ISTA, working with colleagues at the Francis Crick Institute, set out to test a specific hypothesis: Does disorder in that microenvironment promote invasion? To answer it, they built a laboratory model stripped of almost everything except the single variable they wanted to study—geometry. They used microfluidic chips, tiny devices that allow precise control of a cell's physical surroundings. Saren Tasciyan, an ISTA alum and co-first author, designed two versions. In one, pillars were arranged in an orderly, uniform pattern. In the other, they were scattered irregularly, creating a chaotic maze. Tumor cells were introduced to both. The result was unambiguous: in the disordered environment, the cell collective fractured more readily. Individual cells detached and began to invade.

But why? The experimental observation alone was not enough. Hannezo's group, specialists in the physics of biological systems, built computer simulations incorporating basic cell properties—the ability to self-propel, to stick to other cells and surfaces. When cells moved through ordered versus disordered surroundings in silico, the simulations reproduced the experimental findings. More importantly, they revealed the mechanism. Cells do not respond only to the immediate obstacle in front of them at the moment of detachment. They carry a history. As they navigate through a chaotic environment over time, they pass through repeated constrictions and obstacles. This accumulated experience reshapes the boundary of the entire cell collective. The edge becomes rougher, developing finger-like protrusions that weaken the cohesion holding cells together. The researchers call this "collective memory"—a priming effect. Once enough disorder has been encountered, even minor weak points can trigger cells to break free.

The finding points to a principle that extends beyond cancer biology. From a physics perspective, the invasion front of tumor cells follows mathematical patterns that describe seemingly unrelated phenomena—the spreading edge of a coffee stain, the advance of a forest fire. This concept, known as universality, suggests that complex systems can display identical underlying dynamics across different scales and materials. For cancer researchers, the implication is profound: the microenvironment's heterogeneity may be as critical as genetics in determining whether a tumor remains localized or becomes lethal.

Sixt and Hannezo emphasize that genetic factors, epigenetic factors, and environmental factors should not be viewed in isolation. They interact constantly, each shaping the others, collectively determining malignancy. Their work, published in Science Advances, is intentionally framed as a conceptual foundation rather than a final answer. The researchers hope other scientists will take up the approach and test it where it ultimately matters—in real tumor tissue, where the full complexity of the microenvironment cannot be simplified away. That validation remains ahead. For now, the study offers a new lens through which to understand why some cancers spread and others do not: sometimes, it is not the genes that betray us, but the chaos around them.