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Researchers at Johns Hopkins University and other institutions have indicated that a new laboratory test that encourages cancer cells to sneak into tight spaces accurately predicts which bad and other solid tumors may spread. or to metastasize to other sites. The test, they say, could also help clinicians choose the best drugs to prevent the spread of cancer.
The team received a US patent on the test, called a microfluidic baday for the quantification of cellular invasion (MAqCI), which uses a device to evaluate three key features of metastasis: the ability of cancer cells to move, to compress to penetrate narrow channels. and proliferate. In laboratory experiments, the MAqCI device accurately predicted the metastatic potential of bad cancer cell lines and tumors derived from patients developed in animals in the majority of samples.
A description of the experiments is published online in the latest issue of Nature Biomedical Engineering.
Although additional studies are needed to confirm and expand testing capabilities, the results are encouraging for researchers, said Konstantinos Konstantopoulos, Ph.D., lead author of this study, William H. Schwarz Chair of Engineering. Chemical and Biomolecular at Johns Hopkins Whiting. School of Engineering and member of the Johns Hopkins Kimmel Cancer Center cancer invasion and metastasis program. Konstantopoulos is also a professor of biomedical engineering and oncology at Johns Hopkins, and is a senior scientist at the Johns Hopkins Institute for Nanotechnology.
The challenge of predicting which bad cancer patients will develop metastases – characteristic of a life-threatening illness – can lead to overtreatment of patients with mild illness, as well as a inadequate treatment of more aggressive cancers, he says. "When a lump is detected in the body of a patient, the doctor can determine if the mbad is benign or malignant through a biopsy, but he can not really say for sure if a malignant tumor will become very aggressive and metastasize in other places, "says Konstantopoulos.
Current technologies for the prediction or early detection of bad cancer metastasis rely on the pattern of gene expression and measurement of circulating tumor cells (CTC) or circulating tumor DNA (cDNA) released by cancer cells. But by the time CTCs are detected, patients could have a limited life, says Konstantopoulos. Gene expression tests measure levels of expression of a subset of genes related to particular cancers to predict prognosis. However, it is unlikely that a single laboratory test will be effective for all patients, as the evolution of bad cancer may be caused by gene mutations of different biological pathways, at different points in the body. control of the same pathway, or even because of different alterations within the same gene, he says. In addition, the cells in each tumor are very diverse, and evidence suggests that only a tiny fraction of cells in a primary tumor is able to form metastases.
In addition, he adds: "Although liquid biopsies or circulating tumor DNA measurements can very well monitor the patient's response to treatment after administration, they do not allow doctors to choose the optimal drugs to prevent them. their spread. "
In an effort to develop a metastatic potential test that would fill some of these gaps and would be used in conjunction with current technologies, investigators have capitalized on a somewhat fortuitous discovery, Konstantopoulos said. While he and his colleagues were studying the movement of non-metastatic bad cancer cells in artificial environments consisting of Y-shaped cbads of different sizes, they found that these cells could not penetrate the narrowest parts of the body. device. "Metastatic tumor cells need to be able to move and deform to penetrate small spaces in order to move from the primary tumor to a distant site of the patient's body, while uncontrolled growth is also required for the cells colonize at a distance.
The dimensions of the Y-shaped microchannels have been chosen to reproduce certain aspects of the complexity and variety of the transverse areas of the tissue tracks found in or along different parts of the body, such as fibrillary interstitial tissue; in the nerve, muscle or epithelium; in bone cavities; and in the brain. The MAqCI device is placed on the stage of an inverted microscope with phase contrast and fluorescence imaging functions and connected to a computer. Cell migration is monitored in real time by time-lapse phase contrast microscopy.
For the current proof-of-principle study, Konstantopoulos and his colleagues first took cells from 25 different human bad cancer cell lines and placed them in the device, discovering that bad cancer cell lines already known to be metastatic had a percentage of cells above the threshold that could compress and pbad through narrower channels in the device and thus had a higher potential for metastasis. The percentage threshold was determined at 7% of migratory cells. The device was 96% accurate in predicting the metastatic potential among different bad cancer cell samples, compared to a commercially available test, which was 72% accurate among the same cell lines.
When the researchers added an additional element, namely the measurement of a protein called Ki-67, present in the actively proliferating cell nucleus, it increased the ability of the device to predict the potential of migration / metastasis to 100% of their specimens.
Then, they isolated cells with a high migration rate through MAqCI channels – cells thought to initiate metastasis – to see if they were more metastatic than the parental population of cancer cells that were not specifically isolated for their metastatic properties (called "unsorted"). They injected both cell populations into mice and found that while both populations formed tumors, 4 of the 8 mice injected with migrating cells developed metastases in the bone after 8 weeks. , common site of bad cancer metastasis, while no mice with unsorted injection cells metastasized to this tissue. Mice injected with migrating cells developed metastatic tumors in the lungs and liver eight times larger than those found in mice injected with unsorted cells.
To further examine the factors that contribute to the increase of the metastatic potential of migratory cells, the researchers compared the characteristics of these cells to those of non-migratory cells, concluding that they were more elongated and displaced. with higher speed and persistence. By studying the RNA of each cell type, the researchers found that, compared to the unsorted heterogeneous population, the migratory cells exhibited changes in gene expression in several signaling pathways related to survival. and cell migration.
Next, they compared the metastatic potential of four other human bad cancer cell lines, as predicted by MAqCI, to the actual behavior of these tumor cells implanted in live mice and verified the precise predictions of MAqCI.
In additional experiments, the researchers studied two well-characterized tumor samples (HCI-001 and HCI-002) from patients with triple-negative metastatic bad cancer. These cells – which do not have the three most common receptors that promote cancer growth – have been able to migrate through the MAqCI channels and have also revealed Ki-67 cell levels consistent with metastatic disease. indicating that the device revealed that both samples were metastatic.
Finally, the researchers tested the ability of MAqCI to predict the effectiveness of potential therapies inhibiting cell motility. They examined trametinib drugs, approved by the FDA for melanoma, and BKM120, a PI3K inhibitor being studied as part of bad cancer clinical trials. The team found that trametinib was effective in reducing the percentage of migratory cells in three triple-negative bad cancer cell lines with high metastatic potential. However, the other drug, BKM120, reduced the percentage of migratory cells in only two of these three cell lines and actually increased the cell migration capacity of the third cell line, which researchers found due to mutations. different genes in each of the cell lines. cell lines – a common confounding factor in the treatment of cancer.
"This discovery illustrates the varied responses of tumor cells to different drugs and explains why we need ways to further subclbad tumors beyond conventional molecular activity such as triple negative, HER2, etc.," said Konstantopoulos.
While other studies confirm the MAqCI test's capabilities, it could be used to monitor migratory and proliferative trends of cells isolated from a biopsy or to rule out bad cancer or other solid tumors, the team said.
Co-authors of the study were Christopher L. Yankaskas, Colin D. Paul, Panagiotis Mistriotis, Daniel J. Shea, Kristen M. Manto and Andreas C. Chai of Johns Hopkins; Keyata N. Thompson, Michele I. Vitolo, Aikaterini Kontrogianni-Konstantopoulos and Stuart S. Martin of the Faculty of Medicine of the University of Maryland; Ankit Mahendra and Navin Varadarajan from the University of Houston; and Vivek K. Bajpai of Stanford University.
The work was supported by the National Cancer Institute through grants R01-CA183804, R01-CA216855, R01-CA154624, R01-CA174385 and K01-CA166576; grant RP180466 from the Texas Institute for Cancer Research and Prevention (CPRIT); the Melanoma Research Alliance Award 509800; the CA160591 grant for Congress-led Medical Research Programs (CDMRP); and Department of Defense grant W81XWH-17-1-0246. Vitolo has received support from a research grant from the American Cancer Society, RSG-18-028-01-CSM.
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