Researchers at Case Comprehensive Cancer Center uncovered a potentially important role for the protein-coding gene, MYO10, in regulating genomic instability, and in tumor development and immune therapy response. Their findings suggest that levels of MYO10 may indicate which breast cancers are likely susceptible to immune checkpoint blockade (ICB).
The team’s studies in cancer cells and experiments in tumor-bearing mice indicated that breast tumors—including the most malignant triple-negative breast cancers—with high levels of MYO10 responded favorably to immune checkpoint inhibitor therapy, supporting the use of this type of treatment against these tumors. Conversely, the findings also suggested that the use of ICBs should be avoided in breast tumors with low MYO10, because these tumors actually grew larger after ICB therapy.
“This is the first study to link MYO10 with genomic instability and to validate the role of MYO10 in tumor development and immune therapy response,” said research lead Youwei Zhang, PhD, an associate professor of pharmacology at the Case Western Reserve University School of Medicine, and a member of the Molecular Oncology Program of the Case Comprehensive Cancer Center. “We will continue these studies and are eager to see how this knowledge can have a clinical impact on patient care. In addition, we hope that these findings will lead to more effective therapy options for breast cancer patients and the elimination of less effective treatments.”
Zhang and colleagues reported on the results of their research in Science Advances, in a paper titled, “MYO10 drives genomic instability and inflammation in cancer,” in which they concluded, “In conclusion, our results reveal a previously uncharacterized role of MYO10 in tumor development and immune therapy response, highlighting the potential of targeting this gene in cancer.”
Genomic instability refers to the existence of a variety of DNA alterations, which may range from single nucleotide changes, such as base substitution, deletion, and insertion, to chromosomal rearrangements, such as gain or loss of a segment or the whole chromosome, the authors explained. “Loss of genome stability can lead to early onset or accelerate the progression of degenerative diseases including premature aging and cancer.” And while genomic instability is a hallmark of most human cancers, and generally correlates with cancer patient prognosis and the selection of treatment, Zhang and team continued, “…our understanding of how genomic instability is regulated and how it promotes tumor development remains incomplete.”
MYO10 is an unconventional myosin, which previous studies have shown is upregulated in a range of human cancers, with high levels correlating with breast and skin cancer aggressiveness, and indicating poorer patient survival. The collective findings from prior research indicate a potentially important role for MYO10 in cancer development. However, the investigators further noted, “… how MYO10 is regulated and how its up-regulation promotes cancer progression are poorly understood.”
The newly reported research first confirmed that MYO10 is amplified in a wide range of human cancers, and the team also found a positive correlation between MYO10 protein levels and the aggressiveness of breast cell lines, with highly malignant triple-negative breast cancer cell lines expressing the highest level of MYO10.
Their study series also showed that high levels of MYO10 induced chronic inflammation in tumors, which reduced the ability of T cells to slow tumor growth. Yet at the same time, this inflammatory environment in the tumor increased the ability of immune cells to provoke an immune response. This eventually allowed tumor cells to respond to ICB therapy, improving outcomes.
The team uncovered a mechanism by which MYO10 may drive tumor growth. They found that MYO10 regulates genome stability and cancer growth through mediating the nucleus shape. “We showed that MYO10high or overexpression greatly elevated the level of genomic instability in both human and mouse breast tumors,” they wrote. The results also indicated that the level of MYO10 protein is critical for this function. “Here, we report a previously uncharacterized role of MYO10 in maintaining nuclear structural integrity and genome stability.”
The researchers found that high levels of MYO10 increased levels of interferons (IFNs); conversely, low levels of MYO10 correlated with reduced production of interferons. These findings at least partly explain why MYO10-low tumors failed to respond to ICB therapy, they suggested. As the team explained in their paper, “… we observed greatly elevated levels of ILs and IFN response regulators in cancer cells overexpressing MYO10. On the other hand, depleting MYO10 significantly reduced the production of these inflammatory factors.” Interferons and interleukins (ILs)—and other factors that regulate their production—are part of the body’s natural defenses. When they sense germs or cancer cells in the body, they boost the immune system, triggering killer immune cells to fight these invaders.
In conclusion, the investigators wrote, “… our studies propose a model in which MYO10high or overexpression creates an inflammatory tumor microenvironment that leads to T cell exhaustion, which promotes tumor growth … Yet, in the meantime, the immunogenic potential of the tumor environment (i.e., increased genomic instability and the presence of infiltrating T cells) enhanced the tumor response to ICBs.”
Consistent with a chronic inflammation environment in tumors with high levels of MYO10 that led to loss of T cell function, treatment with aspirin to reduce inflammation significantly reduced the growth in mice of breast tumors overexpressing MYO10. This finding is consistent with studies showing that long-term use of aspirin or nonsteroidal anti-inflammatory drugs significantly reduced tumor risk for esophageal, colorectal and stomach cancers, as well as—to a smaller degree—in breast, lung and prostate cancers.
They went on to show how the protein recycling system tightly controls the expression level of MYO10. These findings support the tumor studies, highlighting the importance of MYO10 in tumor development and immune therapy response. “Our findings led us to propose that breast tumors with MYO10high will respond to ICBs,” the team concluded. “On the other hand, they also warn us that tumors with low MYO10 might be resistant to ICBs, and therefore, the application of this type of anticancer agents should be avoided.”