Disease and treatment

Breast cancer defies new medicine and keeps spreading

One of the greatest challenges in the battle against cancer is preventing the cells from the primary tumour from spreading. For decades, researchers have investigated how to inhibit the chemical capacity of cancer cells to break down and squeeze through membranes and tissue structures such as breast tissue – but without success. The researchers now finally understand why their attempts were in vain. Cancer cells also have a second, previously undiscovered, physical method of migrating through tissue. The frontline of the battle is to disable both the chemical and physical mechanisms that cancer cells use.

Treating a person with cancer is often considerably more difficult if the cancer has spread. Metastasis is when cancer cells have escaped from the primary tumour and have pushed their way through the tissue and spread via the blood or lymphatic system. If this happens, the cancer can spread throughout the body, making the battle much harder to win. Some years ago, researchers successfully identified the metalloprotease enzymes cancer cells use to chemically degrade part of the tissue to enable the cells to migrate through it. However, years of effort in trying to prevent this have been unsuccessful. Now there is an explanation.

“We know that cancer cells have a chemical mechanism that helps them to break out of the tissue in which the tumour originated. We have now shown that breast cancer cells can also physically push themselves out of their original tissue and thus become invasive tumours without using the chemical mechanism. This means that simply inhibiting the chemical mechanism of cancer cells cannot stop their progress. We also need to prevent them from physically breaking through the tissue barriers,” explains Ninna Struck Rossen, postdoctoral fellow at Biotech Research & Innovation Centre (BRIC), University of Copenhagen and co-author of the study carried out at Stanford University and published in Nature Communications.

Tiny stiff arms

The discovery is based on inventing a special combination gel that physically resembles the tissue in a woman’s breast. This biologically active hydrogel comprises reconstituted extracellular matrix. By combining this hydrogel with alginate, another hydrogel derived from algae that is biologically inactive, the researchers created a structure that closely resembles breast tissue. In addition, the physical properties of the hydrogel can be changed without changing its chemical properties. In particular, the plasticity of the combination hydrogel can be regulated independently of how stiff it is.

“The alginate is not broken down by the chemical mechanism that cancer cells use to migrate through tissue. We were able to examine how the cancer cells, similar to migrating through tissue in the body, could still migrate through the combination gel. We thereby showed that the cells must have another mechanism for penetrating tissue. We also confirmed that the cancer cells retained their ability to penetrate the tissue, even when they were exposed to protease inhibitors that blocked the chemical mechanism.”

The researchers used microscopy to follow how the cancer cells penetrated the tissue to try to determine how the cells could migrate through the hydrogel without using the chemical mechanism. The images obtained showed that invadopodia on the surface of the cancer cells assisted this migration.

“The process could be described as tiny stiff arms that push, create and expand small holes in the hydrogel. After a couple of hours, the cancer cells had created an opening that was big enough to enable them to squeeze through, and they used this method to gradually work their way through the tissue. Although the process was much more rapid when the cancer cells had both chemical and physical mechanisms, the physical mechanism was sufficient.”

Stiff tissue can promote cancer

These new results may turn out to be a major breakthrough, because for decades researchers have tried to hinder metastasis by inhibiting the protease enzyme of cancer cells: the chemical mechanism for breaking down tissue. However, this strategy has been very disappointing. The new research explains not just why but also provides clues for possible future strategies.

“Protease inhibitors cannot be used alone but must be combined with equivalent mechanisms to combat the physical capacity of cancer cells such as the invadopodia. My colleagues at Stanford Medicine and Stanford Engineering are therefore actively developing a new strategy for blocking both the physical and chemical mechanisms cancer cells use to escape, which may be a new way to combat cancer.”

Because the new hydrogel is so similar to human tissue, the experiments also revealed a previously unknown process. Cancer tissue is actually malleable. In addition, if the physical forces of the cancer cells influence the tissue, it can change and become stiff. This stiffness turns out to promote the spread of the cancer cells.

“Our research shows that cancer cells become more aggressive in stiff tissue and are therefore better at penetrating it. The way cancer cells physically affect tissue can also change it, increasing the likelihood that the cancer cells will migrate. So finding a method to keep this tissue soft – during cancer treatment – might also avoid metastasis.”

Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments” has been published in Nature Communications. In 2015, the Novo Nordisk Foundation awarded a visiting scholar fellowship at Stanford Bio-X to Ninna Struck Rossen, Biotech Research & Innovation Centre (BRIC), University of Copenhagen.

Ninna Struck Rossen
International Researcher
Metastases are responsible for over 90% of cancer patient deaths. Understanding how tumours acquire the ability to invade and metastasise is critical for the identification of new targets and development of therapies against metastatic disease. Metastasis is a multistep process influenced by the immediate microenvironment, specifically cell-cell and cell-matrix interactions, and by the extended microenvironment, such as vascularity and tissue stiffness. A major theme of our research is to take an interdisciplinary approach to investigate cancer progression. Almost all projects in the lab use systems wide approaches to help investigate questions. We believe that interdisciplinary research can advance our knowledge in ways that are not possible using single disciplinary or conventional approaches to scientific research. We study cancer spread using a variety of approaches, and aim to investigate effects on the whole biological system rather than a few selected components. To do this, we use multiple global, unbiased methods, such as mass spectrometry-based proteomics, phosphoproteomics, kinase profiling, transcriptomics, DNA methylation and genomics in our work. We also use cross-disciplinary approaches, for example we have a project to understand the physics of cancer cells during invasion, using mechanical tweezers and advanced microscopy to measure forces.