ABOVE: A stained section of an invasive breast cancer growth Lars-Christian Horn

Tumors are notorious for being harder than normal tissue, making them possible to identify through palpation. However, scientists who study individual cancer cells have found that the cells are soft—softness that is required for tumors to metastasize by squeezing through surrounding tissues and vessels en route to colonizing new locations. The paradoxical character of tumors that are simultaneously soft and yet hard to the physician’s touch has mystified scientists and clinicians for decades.

But now, after more than six years of back and forth with peer reviewers and journals, an international team of researchers across multiple scientific and medical fields says they’ve solved the enigma: Tumors are both hard and soft. “Islands” of rigid tumor cells are interwoven in a “sea” of fluid cells, the team reports September 29 in Nature Physics. This special arrangement makes cancerous growths tough enough to push against the surrounding tissues as the tumor grows but soft enough to allow metastasis. The findings could lead to a new prognostic marker for cancer patients, the scientists behind the work say, helping ensure those with lower metastatic risk don’t needlessly undergo taxing treatments.

“This is a very impressive amount of work,” says Paul Janmey, a biophysicist at the University of Pennsylvania who wasn’t involved in the study. “It’s a culmination of a lot of effort by both the experimental people and the theorists.”

University of Leipzig physical oncologist Josef Käs, together with a team of nearly thirty scientists ranging from physicists to clinicians to imaging experts, set out to crack the case of the soft-celled hard tumors, and figure out exactly how apparently soft cells obtain their rigidity.

Käs and the other physicists on the team had a hunch that the solution was related to a physical phenomenon called jamming: where a substance like sand, for instance, flows easily in an hourglass but becomes “jammed” when pressure is applied, which is what allows a person to stand on it at the beach. Few had thought to apply this physical concept to organic matter, they say—but to do so for tumors would prove no simple feat. To test for jamming properties in cancer, Käs and the team needed to examine tumors at multiple scales: single cells, cell clusters, and the tumor in its entirety. And that required a suite of methods.

At the tumor scale, the team used magnetic resonance elastography (MRE)—an MRI for cells that uses sound waves and imaging to determine their chemical properties—on centimeter-sized tumors taken from mammary and cervical carcinomas. “If you want to understand the mechanical features of a piece of tissue, it’s not enough just to take the macroscopic piece of tissue and put it in a device that gives you a modulus [of rigidity],” Janmey says. “Magnetic resonance elastography could be much better than that because it can look at things in vivo and at a better spatial resolution.”

It’s a devilish thing. As a materials scientist, it’s exciting to find this new weird state of matter. As a human, it scares you. 

—Josef Käs, University of Leipzig

At the cell cluster level, the researchers used atomic force microscopy (AFM) to perform cell indentation on the same mammary and cervical tumors, prodding individual cell clusters and observing their elasticity. In previous studies, scientists were performing these tests in the dark: They couldn’t distinguish whether they were prodding connective or cellular tissue. Käs and the rest of the team used a novel fluorescent dye called SPY-DNA to visualize the nuclei of each cell, allowing them to see the types of cells they were testing in real time.

Then, at the single-cell level, they used an optical cell stretcher to pull individual cells apart, gathering information on each cell’s mechanical behavior and how it varied amongst different cell types within a single tumor. With all three scales of elasticity testing, Käs and the team could build a complete picture of the cells that make up tumors.

The multiscale testing revealed that an average of 75 percent of the cells in each tumor were soft. The rest, which were rigid, sat in clusters evenly distributed throughout the tumor. These rigid cell islands collectively created tension between the softer surrounding cells, causing the entire tumor to “jam” against external forces even though the majority was composed of soft cells. This setup ensures that tumors can push healthy tissue out of the way as they grow. Meanwhile, the soft cells can still behave as a fluid, allowing them to squeeze through the surrounding tissue and metastasize.

“It’s a devilish thing,” Käs says. “As a materials scientist, it’s exciting to find this new weird state of matter. As a human, it scares you how perfectly cancer tunes single-cell properties and tunes collective properties. This is really the optimal state for it to expand and metastasize simultaneously.”

Janmey says that this study is a big step towards understanding tumor-cell interactions, and the importance of cell positioning rather than just the mechanical properties of the cells themselves. “The concept that a cell’s functioning depends so much on its local neighborhood is being increasingly recognized as an important idea,” he says.

Käs says he hopes to use this new finding to better predict cancer patients’ prognoses, ensuring treatments such as chemotherapy that often come with severe side effects are only given to those that need them most. Knowing that only the fluid tumor cells metastasize, Käs says scientists could potentially measure the percentage of fluid cells within a tumor to determine the metastatic risk more accurately than previous markers. Increased accuracy in measuring metastatic risk could keep those with low risk out of debilitating treatment regimens, vastly improving their quality of life, he says.

However, these cell interactions are complicated, he says, and more research is needed to properly understand them before the findings can become incorporated in clinical practice.

“The picture is not black and white,” Käs tells The Scientist. “Seeing that interplay between high proliferation, high motility, and emerging new phenotypes, it will be highly interesting to see how cancer will advance.”