Researchers have identified a novel mechanism by which triple-negative breast cancer (TNBC) cells enhance their ability to metastasize, or spread to other parts of the body. This discovery, published in , in Nature Communications, offers potential new avenues for developing targeted therapies for this aggressive form of breast cancer, for which treatment options are currently limited.
Metastasis is the primary driver of cancer-related deaths, and understanding the processes that enable cancer cells to spread is crucial for improving patient outcomes. As Dr. Chonghui Cheng, professor of molecular and human genetics and molecular and cellular biology at Baylor College of Medicine, explains, “Metastasis occurs when cells break away from the main tumor and travel through the bloodstream to spread to other parts of the body where they can seed new growths.” Circulating tumor cells (CTCs) are more effective at forming new tumors when they travel in clusters rather than individually, as clusters offer increased survival and a greater ability to establish themselves in new organs.
A long-standing question in TNBC research has been how these cancer cells form stable clusters, given that they often lack the proteins responsible for strong cell-cell adhesion. Typically, adherens junction (AJ) proteins are essential for maintaining the integrity of these clusters. However, these proteins are frequently lost in highly aggressive TNBCs, creating a paradox: how do CTCs cluster if they lack the necessary adhesion molecules?
The research team, led by Dr. Cheng, investigated this question by comparing TNBC cells to non-TNBC cells and examining both metastatic and non-metastatic breast cancers. Their analysis revealed a significant role for the extracellular matrix (ECM), particularly a component called hyaluronan (HA). The ECM is a complex network of proteins and carbohydrates that surrounds cells, providing structural support and facilitating cell communication.
“When we analyzed the data, the extracellular matrix stood out, particularly hyaluronan (HA), one of its components,” said co-first author Dr. Georg Bobkov, instructor in the Cheng lab. HA acts like a ‘sticky coat’ around cells, and the researchers found that TNBC cells produce unusually high levels of HA, effectively coating themselves with this molecule. This HA production is driven by an enzyme called HAS2.
Further investigation revealed that HA plays a critical role in cluster formation. When HA was removed from CTCs, the clusters disintegrated. The researchers also discovered that HA interacts with a cell surface protein called CD44. Without CD44, HA cannot be effectively presented on the cell surface, and cells are unable to cluster. “When we removed HA from CTCs, the clusters did not hold together. We also found that HA works with a cell surface protein called CD44. Without CD44, HA cannot be presented on the cell surface and cells cannot cluster,” explained co-first author Dr. Khushali Patel, a postdoctoral fellow in the Cheng lab.
The stability of these HA-mediated clusters is further enhanced by another set of proteins called desmosomes. This combination of HA, CD44, and desmosomes allows TNBC cells to form robust clusters that can withstand the stresses of circulating in the bloodstream, protecting them as they travel to distant sites.
Interestingly, HA-mediated clustering offers advantages beyond simply holding cells together. Unlike the rigid clusters formed by AJ proteins, HA creates more flexible clusters. This flexibility is particularly beneficial when navigating the body’s circulatory system. “There is another benefit from the HA-based clustering. While AJ-mediated clustering is rigid, HA mediates the formation of more flexible clusters, which become an advantage in certain situations. We knew from other studies that when CTC clusters travel through very narrow blood vessels called capillaries, they do so in a single-cell file in which the cells stay in contact. They reform the cluster after they pass the capillaries. Our findings found an explanation for this behavior. The flexible nature of HA-mediated clustering allows CTC clusters to disassemble temporarily while the cells cross a narrow path and reassemble into the protective cluster afterward,” Dr. Bobkov noted.
The researchers also found that HA-mediated clustering can incorporate other cell types, including immune cells. Specifically, they observed that neutrophils, a type of immune cell, are attracted to and captured by the HA coating on CTC clusters via interactions with CD44 on the neutrophil surface. “Some of the immune cells in clusters, like neutrophils, protect CTCs, but we did not know how clusters sequestered neutrophils,” Patel said. “Neutrophils express CD44 on their surface. HA on clusters can bind to it, capturing neutrophils.”
While further research is necessary, these findings suggest potential therapeutic strategies. Dr. Cheng and her team propose that blocking the interaction between HA and CD44 could prevent the formation or disassembly of CTC clusters, thereby reducing metastasis. “One idea is to develop ways to prevent the formation of or to disassemble CTC clusters by blocking the binding between HA and CD44, which we expect would prevent or reduce metastasis,” Cheng said. The researchers observed HA-CD44-mediated clustering in other aggressive cancers, including glioblastoma, prostate cancer, and pancreatic cancer, suggesting that these therapies could potentially benefit a broader range of patients.
This research highlights the complex interplay between cancer cells and their surrounding environment, and underscores the importance of considering the ECM in the development of new cancer treatments. The study was supported by multiple grants from the National Institutes of Health (NIH), the Cancer Prevention Research Institute of Texas, and other funding sources.
