Follow the leader (cells)

Scientists develop microfluidic device to track the cancer cells that break off from original tumors to seed metastases elsewhere in the body

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The spread of cancer (metastasis) is one of the biggest—and most difficult—issues of the disease. In fact, it's usually not the original primary tumor that kills cancer patients, but the cancer metastasizing to other parts of the body. Researchers know that metastasis is the result of individual cancer cells becoming more aggressive and separating from the primary tumor to spread through the bloodstream to secondary sites, but questions remain as to how exactly these 'leader' cells differ from regular tumor cells and whether they can be identified and blocked.
In hopes of shining some light on the issue of these leader cells, a release penned by Nicole Fawcett of the University of Michigan Comprehensive Cancer Center shared news that scientists from the Center and Michigan Engineering have designed a new microfluidics device, and recently published their work in Scientific Reports in a paper titled “Tracking the tumor invasion front using long-term fluidic tumoroid culture.”
The Michigan team's design differs from typical fluidic devices in a few ways. For one, they needed to develop something that would allow them to cultivate cells for long periods, since cancer cells change over time and cells only last a matter of days in existing microfluidic devices. This new device, by contrast, was stable up to at least three weeks in culture. In addition, cells in this device are suspended in three dimensions, compared to the usual two dimensions of standard fluidic devices, which enabled the team to direct cancer cells into the device with minimal disturbance or alteration to the cells. It features a trio of tiny, molded channels that cells flow through—cells are fed into one channel, while fluid flows through a parallel channel to provide pressure and flow in a way that mimics how fluids flow through capillaries in the body.
“A lot of tumor processes like invasion and resistance don’t happen overnight. Our goal was to track the long-term evolution of invasion. We cannot look at just a certain time point, like in a three-day experiment. That might not represent what’s happening in the body over time,” said lead study author Dr. Koh Meng Aw Yong, a postdoctoral fellow in the lab of study author Dr. Sofia Merajver, scientific director of the Breast Oncology Program at the Comprehensive Cancer Center.
For this study, the team used two kinds of prostate cancer cells, DU145 and PC3, to form a tumoroid that was 500 μm in diameter. The authors noted in the paper that “Excitingly, this 3D tumoroid culture model was able to recapitulate in situ features of tumor invasion including the invasion front which can be preserved, processed and stained using conventional immunohistochemistry.” PC3 cells were found to be more invasive than DU145 cells “as determined by the maximum invasion distance (defined as the longest distance from a leader cell to channel B) in the first two weeks of culture, consistent with the known invasive potential difference between the two cell lines.” However, while the PC3 cells were roughly twice as invasive as the DU145 cells at 12 days of culture, “this difference was rapidly lost by 3 weeks, suggesting that the invasive potential of cells may change over time.”
They also found that the invading cells of tumors are more proliferative than those in the interior after they stained and examined sections of the tumoroids for Ki-67, “a molecular marker of cell proliferation and metastasis.” The paper noted that “it has been reported in different patient tumor types that Ki-67 positive cells preferentially locate at the invasion front, suggesting a correlation between Ki-67 expression and invasion.” In keeping with that, the team reported that “We further observed prominent Ki-67 staining mainly localized at the interface between the tumoroid and collagen or in invading cells in both PC3 and DU145 tumoroids. This observation, which is consistent with clinical findings, again supports a positive correlation between proliferation and active invasion.” The presence of growth differentiation factor 15 (GDF15) was also investigated, as elevated serum levels of this protein have been seen in patients with metastatic prostate cancer and is often linked to a poor clinical outcome, as noted in the paper. As with Ki-67, further examination showed that “GDF15 expression was higher in invading cells than those inside the tumoroid, suggesting an association between GDF15 expression and invasion.”
In addition to elucidating characteristics of leader cells, it's thought that this device could also be used to monitor patients while they undergo treatment, according to Aw Yong, as “The device would be able to show us if the cells become more aggressive before a traditional imaging test would detect anything.”
“The device also holds potential to be used to test drugs and detect when cancer becomes resistant. This would allow oncologists to know sooner if a therapy is not working and perhaps switch the patient to another option,” added senior study author Dr. Jianping Fu, associate professor of mechanical engineering at the University of Michigan. “Of course, more research is needed to explore this possibility in the future.”
The next target for this approach is triple-negative breast cancer, which is also known for being a highly aggressive type of cancer.

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