GOTHENBURG, Sweden—Cancer metastasis is more often the cause of death than a patient’s initial tumor, and work is still ongoing to discover exactly how this process occurs and what triggers it. Previous work has shown that one culprit in this process is “leaky” blood vessels, through which cancer cells that break off from a tumor can travel through the bloodstream to other locations, and now a new instigator has been identified by a research team from Chalmers University of Technology: the Antioxidant 1 copper chaperone (Atox1).
Their study, “Single-cell tracking demonstrates copper chaperone Atox1 to be required for breast cancer cell migration,” was published in the Proceedings of the National Academy of Sciences (PNAS).
Atox1, which is found in breast cancer cells, is a copper-binding protein. It has been previously established that many cancer types, including breast cancer, present with higher levels of copper in the blood and tumor cells. In normal cellular states, Atox1 is responsible for transporting copper to other proteins in human cells that need the mineral to function, as the mineral plays a role in processes such as “cellular respiration, protection against oxidative stress, biosynthesis of chemical messengers, modulation of connective tissue, and pigment construction,” according to the PNAS article. In the case of cancer, Atox1 is found on the leading edge of traveling cancer cells.
“We were able to demonstrate that the cells moved at higher speeds and over longer distances when Atox1 was present, compared to those same kinds of cells moving without the protein,” reported Stéphanie Blockhuys, who is a postdoctoral researcher in Chemical Biology at Chalmers and first author of the study.
Atox1 was found to kick off a chain reaction that involves ATP7A, another copper transport protein, and the enzyme lysyl oxidase. Atox1 transports copper to ATP7A, which then transports it to LOX, which needs copper to function. As noted in the paper, “Cancer cells secrete LOX to create premetastatic niches by stimulating collagen cross-linking and fibronectin synthesis that in turn promote tumor cell migration and adhesion. In addition to extracellular activities, LOX may also regulate cancer cell migration via (less-known) intracellular activities, such as modulation of actin polymerization ... Since LOX is an established player in cancer cell migration, our results imply that Atox1 mediates breast cancer cell migration via coordinated copper transport in the ATP7A-LOX axis.”
“When Atox1 in the cancer cells was reduced, we found LOX activity to be decreased. Thus, it appears that without Atox1, LOX doesn’t receive the copper required for its cell migration activity,” added Blockhuys.
In addition to their microscopy tracking of Atox1 proteins, the team also looked at reported Atox1 transcript levels and survival times in 1,904 breast cancer patients. Patients whose tumors presented with high Atox1 levels were found to have significantly lower. The team also reported in their paper that in addition to breast tumors, upregulated Atox1 is also seen in colorectal, uterine and liver tumors.
As for future work in this vein, the team is advancing into small animal models to determine if additional copper-binding or transporter proteins other than Atox1 and ATP7A play a role in metastasis. In addition, the authors postulated that Atox1 could also play a role in disease prognosis, noting that “Atox1 may act as a biomarker for breast cancer metastasis, such that patients with high Atox1 levels in primary tumor cells are at higher risk of metastasis than those with low Atox1 levels. Patients with high Atox1 would benefit the most from copper chelation therapy, which is an approach currently under investigation in clinical trials.”
“In connection with clinical studies, quantification of migration properties of cancer cells using time-lapse microscopy may be a useful tool in the study of potential therapeutic anticancer drugs as well as in the discovery of molecular pathways of metastasis,” they concluded.
New biomaterial has potential for surgical interventions
By Kelsey Kaustinen
In other news from Chalmers, though more on the medical technology side of things, the university announced earlier in the year that it had created a rubber-like material that could serve as a replacement for human tissue in surgeries and other procedures. The study, “Tough Ordered Mesoporous Elastomeric Biomaterials Formed at Ambient Conditions,” appeared in ACS Nano.
As has happened with other discoveries over the years in many fields, the scientists developed this material while trying to create something entirely different. The material has the same foundation as plexiglass, which already features in medical technology, and by redesigning it via nanostructuring, they hoped to create something that could serve as a replacement for bones. The rubber-like end result, however, still has significant potential—the material is flexible, highly elastic, easily processed and viable for medical use.
Additionally, this material can be injected through a cannula as a viscous fluid, after which it would form its own structures in the body, or it can be 3D printed into specific configurations. It also contains nanopores that could be filled with medicine for localized treatment or, in the case of surgery such as disc or cartilage repair, to encourage healing and reduce inflammation. Even more promising, its surface can be treated to render it antibacterial simply by attaching antimicrobial peptides—part of the innate human immune system—to the surface.
“The first application we are looking at now is urinary catheters. The material can be constructed in such a way that prevents bacteria from growing on the surface, meaning it is very well suited for medical uses,” said Martin Andersson, research leader for the study and professor of chemistry at Chalmers.
The Chalmers team is looking to advance this into the market as quickly as possible. To enable that, the researchers patented this new material, and the patent is owned by Amferia, a startup founded by Andersson, fellow study participant Anand Kumar Rajasekharan and Chalmers researcher Saba Atefyekta.