March 19, 2025 | Based on the discovery that the adhesion strength of cancer cells scales inversely proportional to the invasiveness of a tumor, researchers at University of California, San Diego have built a microfluidic device with the hope that it can be used in the future to diagnose the metastatic potential of ductal carcinoma in situ (DCIS) breast cancer tumors. “Animal models show that the weaker the cells’ adhesion is, the more migratory they will be and the more likely they are to develop into a secondary metastasis,” says Adam Engler, Ph.D., a bioengineering professor at the UC San Diego Jacobs School of Engineering.
Fresh evidence of that comes from a study in mice that was published recently in Cell Reports (DOI: 10.1016/j.celrep.2025.115359), from Engler’s lab and co-first authored by Madison Kane, a bioengineering Ph.D. student. She is credited with the human patient sample study design and hands-on work with the device, where fluid flow is controlled via a diamond-shaped chamber with graduating degrees of sheer stress, to measure the adhesion strength of patient tumor cells.
The study looked at nine cancerous/non-cancerous mammary epithelial cell lines and tissue from patients with invasive lobular/ductal carcinoma, DCIS, as well as healthy breast tissue. Patients with DCIS were by far the most heterogenous when it came to their adhesion strength, says Kane, in referring to the propensity of cells to either cling or escape from the primary tumor microenvironment and invade surrounding stroma. DCIS is a very early “stage 0” breast cancer where cancer cells are confined to the milk ducts, and at present, it is difficult to forecast which patient’s cancer is likely to metastasize.
It’s more clear-cut with other breast cancers where sizing and grading are more predictive of a tumor’s behavior, points out Engler. For low-grade tumors, adhesion strength may be a promising functional marker that could help the medical community identify patients who will or will not respond to the normal therapeutic regimen (surgery, radiation therapy, and potentially hormone therapy) so they can adjust their treatment plans accordingly.
“One of the problems with a lot of biomarkers these days [e.g., estrogen receptor, progesterone receptor, HER2, BRCA1 and BRCA2] is that they are specific for a given tumor,” Engler says. Adhesion strength is likely applicable to all solid tumors, since to metastasize they all need a means for cellular migration through some other tissue to access the vasculature and spread to a new location in the body.
A patent on the device measuring this behavior of cells was just issued in January, adds Engler. By the end of the spring quarter, a startup could launch to move the research into clinical trials, the five-year goal being clearance of the diagnostic by the U.S. Food and Drug Administration (FDA).
As demonstrated in the study, patient cells derived from invasive lobular or ductal carcinoma cancer tissue are less sticky than cells from non-invasive DCIS cancer (with varied adhesion strength) or completely normal mammary tissue (most strongly adherent). The hypothesis is that DCIS patients with very weak adhesion strength as measured by “tau”—a mechanical engineering term relating to the amount of stress applied to a cell that causes it to detach—may be the patients who need closer monitoring because their disease could become metastatic later, says Kane.
Engler has two analogies for the relationship between adhesion strength and a cancer’s metastatic potential, one of which he likens to the fairy tale “Goldilocks and the Three Bears.” Like porridge that is neither too hot nor too cold for eating, cells that are “just right” in terms of adherence can “grab to their environment, polymerize, and push forward, and then rebind and make a new adhesion.”
The adhesion strength of cancer cells might alternatively be compared to driving on a wet road or hot asphalt where the tires hydroplane or expend greater energy to spin versus being in an optimal range where they have just the right amount of grip to propel the vehicle forward. “The same idea is true for cells,” he says. “You don’t want them to be so weak that all they do is slip, and you don’t want them glued to the environment as if stuck in concrete. You want the cells to be just right where they can push forward.”
The vision is to use adhesion strength as a physical marker to identify DCIS patients at the outset of treatment whose cancer has high metastatic potential tied to their survival outcomes, Engler says. About one in five women with breast cancer have DCIS, which is slightly more than those diagnosed with the more aggressive triple-negative breast cancer (about 10% to 15%), but at least oncologists know how to proceed with the more invasive cancer subtypes.
With DCIS, “our device may fill that gap to provide... an additional metric to examine when oncologists are trying to make an informed recommendation to patients,” says Engler.
He and his team started investigating the adhesion strength of tumor cells about a decade ago after observing that different breast cancer cell lines migrate differently, and the faster they traveled the more quickly “adhesion turnover” (dynamic process of cell adhesion molecules assembling and disassembling) happened, he explains. So, they decided to put the breast cancer cell lines into an adhesion assay that was to become an early precursor to the one used in the latest Cell Reports paper.
That led to the publication of a study in the Biophysical Journal (DOI: 10.1016/j.bpj.2016.12.038) suggesting that adhesion strength may serve as a general marker of metastatic cells. Scientific interest in physical differences between tumors piqued around 2010 when the National Cancer Institute launched a funding mechanism called the Physical Science-Oncology Projects (PS-OP) to “move beyond” biological markers that characterize tumors and instead look for physical differences that might further reflect differences in patient outcomes, says Engler.
PS-OP made it feasible for physicists and engineers to study things “like adhesion and how adhesion may be a useful functional marker for breast cancer as well as other cancers,” he says. Adhesion in general is a relatively large area of study that extends also to watching how immune cells circulating in the bloodstream dynamically regulate the process and invade tissues to mount a counterattack against a perceived enemy.
In terms of the new diagnostic assay, the novelty lies in the geometry of the chamber, which impacts the path of fluid flow through it, says Kane. The diamond shape “allows us to achieve a gradient of shear stress in our channel so cells experience anywhere from a very low shear stress [wider portion of the chamber] to a very high shear stress [narrower portion], giving us an idea of what percentage of the cells are being sheared off and at what shear stress.”
Since the study only utilized 16 human patient samples, stratification was limited to higher versus lower adhesion strength, adds Engler. A larger clinical trial with hundreds of patients would allow researchers to better stratify the patient population with a risk score based on how low the “tau 75” score is, which may reflect the likelihood of a DCIS tumor becoming metastatic. Tau 75 refers to shear stress at which 25% of cells shear off the device, explains Kane.
Once the startup company is established, it will take over further development of the diagnostic device, including plans for a prospective clinical trial. Participants, potentially including the 16 in the initial study, will need to be monitored over the course of several years, he says.
The trial would be a larger version of the just completed one involving an experimental group of patients with DCIS alongside healthy controls, patients with full-blown metastatic disease, and five-year follow-up. Since it is testing a functional biomarker, it must be done prospectively on freshly isolated cells from live tumors, continues Engler. “We don’t have the benefit of going into the biobank here at the Moores Cancer Center [at UC San Diego Health]... or any other cancer center across the country and pull out tumors that were frozen from patients 10 years ago.”
That study is therefore going to take five years to complete, he says. If the device demonstrates some predictive capability, researchers will use the evidence to seek FDA clearance to market the diagnostic.
“I think the real selling point from a commercial perspective will be that such a device could be deployed to all sorts of solid tumors,” says Engler. “We are looking beyond breast cancer to other epithelial carcinomas, at least to start with, and that would include things like lung cancer and prostate cancer.”
Cell lines obtained from both of those tumor types behave the same way as breast cancer cells, he notes. Some weakly adhered fractions within the same population migrate faster than others.