Closing the "tunnel of cells" to slow cancer

Recent research has uncovered an especially aggressive mechanism for the spread of a particularly aggressive type of breast cancer, in which the NUP93 protein plays a key role. Because this protein creates a "tunnel" in the nuclear membrane, the cancer can gain access to the cell's DNA and exploit it to satisfy its own goals, such as increasing the cell's ability to migrate and spread the disease more quickly.

It is frequently more difficult to cure cancer that spreads quickly, but understanding the molecular basis of this aggressive malignancy could lead to the development of novel drugs to treat these tumors in the future. Researchers at the Weizmann Institute of Science have discovered a mechanism that explains the spread of a particularly aggressive type of breast cancer, in partnership with the National Cancer Institute and other institutions.

A related study was recently published in Cell Reports, entitled "Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors".

The research began with a large-scale computational analysis of data from numerous databases, including information on patient survival and hyperactive genes in cancer that is aggressively spreading. The researchers identified roughly 20 genes, out of a total of about 25,000, that appear to be required for the spread of the most aggressive breast cancers. The first two genes are involved in cell division and have previously been exploited as anti-cancer drug targets. The third, however, perplexed the researchers because it encodes a protein called NUP93, which is found in the envelope that surrounds the nucleus and is one of the numerous components of the pores or tunnels.

NUP93 is detected in exceptionally high levels in breast cancer patients with the poorest survival rates, according to researchers. Some of these patients' genomes had 2 or 3 copies of the NUP93 gene instead of the usual number of copies as the disease progressed. Surprisingly, many of these patients' tumors are estrogen-insensitive. Because they lack the estrogen receptors targeted by hormonal anticancer drugs, these tumors, which account for about one-third of all breast cancers, are particularly difficult to treat.

"Understanding what causes these malignancies is extremely important because we currently have limited treatment options," stated study team leader Professor Yosef Yarden of the Weizmann Institute of Science's Biomodulation Unit.

The scientists confirmed that there is a relationship between high levels of NUP93 and cancer aggressiveness by conducting laboratory experiments that mimicked what happens in patients. When breast tissue cells were genetically engineered to produce no NUP93 at all, they remained dormant. Instead, genetically engineered cells had multiple copies of the gene, resulting in high levels of the NUP93 protein, which became extremely mobile and resembled metastatic cancer cells that spread to distant organs. Unlike cells lacking the protein, cells with high amounts of NUP93 spread to the lungs in mouse experiments. Even without modifying the number of genes, the researchers discovered that adding a mutant form of NUP93 into the cells lowered the rate of cell migration.

Next, the scientists unraveled the mechanism by which NUP93 plays a dreadful role in cancer. Because this protein forms a tunnel in the nuclear membrane, it allows the passage of shuttle proteins called importins, which, in their cargo load, transport growth and migration instructions from the cytoplasm to the nucleus and thus to DNA. In this way, cancer can enter the cell's genome and use it for its own needs, namely to increase cell migration and accelerate its ability to thereby spread the disease.

Yarden explained, "cancer needs a highway to the nucleus so that growth signals from outside can quickly reach the genome. The more NUP93 tunnels on the way, the faster the signal can travel and the greater the metastasis in the patient's body."

Disrupting the process of metastasis, which is the leading cause of death in breast cancer patients, is a viable route for creating potential therapies. However, totally shutting down NUP93 tunnels is unrealistic since they perform many critical roles in healthy cells, such as transmitting wound-healing signals.

Therefore, Weizmann's scientists tried a different approach—preventing the delivery vehicle importins from loading lethal cargo, i.e., increasing cell mobility. In mice tests, blocking small peptides of specific, relevant importins greatly reduced the ability of cells to migrate and cause metastasis. These discoveries could pave the way for the development of a drug that could one day allow for the treatment of even the most aggressive forms of breast cancer.