When skin cancer metastasizes, individual cancer cells leave the tumor and travel throughout the body. To get into the bloodstream, however, they have to squeeze through narrow gaps in the tissue. A stable cell nucleus is a hindrance. A study now shows that a protein called LAP1 is enriched in aggressive skin cancer cells. This allows the cells to deform their nucleus and thus become narrower. The results might help to find new approaches to prevent metastases.
Black skin cancer is usually easy to treat in the early stages by removing the melanoma that is visible on the skin. However, it becomes problematic when the cancer spreads to other areas of the body and forms metastases. These are the leading cause of skin cancer-related deaths. However, before cancer cells can leave the primary tumor, they have to overcome physical barriers: In order to get out of the dense tumor tissue and into the blood or lymphatic system, they have to squeeze through narrow spaces – so narrow that a normally shaped cell nucleus would be too large. But how do they manage to get to other parts of the body?
A team led by Yaiza Jung-Garcia from the Francis Crick Institute in London has now investigated this question using patient samples and laboratory experiments. First, Jung-Garcia and her colleagues simulated metastasis in the laboratory. To do this, they created an artificial membrane with pores that were smaller than the usual size of a cell nucleus. Then they tried to let aggressive and less aggressive melanoma cells migrate through this membrane. The aggressive cancer cells came from metastases of skin cancer patients, the less aggressive from the primary tumor.
Softened nuclear envelope
The result: the aggressive tumor cells were able to move through the tiny pores much more effectively than the less aggressive ones. With the help of imaging methods, the research team made the trick used by the cancer cells visible: while the cell nucleus actually has a stable shape in order to optimally protect the genetic material it contains, the aggressive melanoma cells apparently temporarily soften the structure. Small, bubble-like protuberances form at the edge of the cell nucleus and it becomes narrower overall. After the cell has passed through the pore, the original cell core structure is repaired within around ten minutes. The researchers found no evidence that the passage resulted in an increased rate of cell death.
In order to find out what gives the aggressive tumor cells this ability, Jung-Garcia and her colleagues examined which proteins are found in these cells. “We discovered an increased concentration of the so-called lamin-associated polypeptide 1, LAP1 for short,” the researchers report. This protein is found on the inside of the membrane that surrounds the cell nucleus. “Our investigations show that the LAP1 protein loosens the bonds in the membrane, so that the nuclear envelope can bulge and bubbles can form, which make the cell nucleus more fluid,” explains Jung-Garcia’s colleague Jeremy Carlton. “As a result, the cancer cells were able to squeeze through gaps that would normally stop them.” If the research team blocked the production of LAP1 in the aggressive cells, they were significantly less able to form bulges in the nuclear envelope and diffuse through narrow pores .
Biomarkers and therapeutic approach?
The researchers believe that the LAP1 content in tumor cells might possibly represent a marker that provides information regarding the prognosis of a melanoma patient. According to the results, patients whose cells had an increased level of LAP1 had a higher risk of an aggressive disease and a poor course. “Our study provides a new mechanistic understanding of how LAP1 contributes to melanoma progression,” says co-author Victoria Sanz-Moreno of Queen Mary University in London. “We have shown that LAP1 is an important regulator of melanoma aggressiveness in laboratory and patient models.”
The findings might possibly also inspire future cancer therapies. “Because LAP1 is expressed at such high levels in metastatic cells, interfering with this molecular machinery might have major implications for cancer spread,” says Sanz-Moreno. “Currently, there are no drugs that directly target LAP1. Therefore, in the future we would like to investigate how to target LAP1 and nuclear envelope blistering to see if it is possible to block this mechanism of melanoma progression.” use similar mechanisms, such as immune cells. With this, the team wants to find out whether LAP1 might be involved in other cells in preventing the progression of the tumor.
Quelle: Yaiza Jung-Garcia (Francis Crick Institute, London) et al., Nature Cell Biology, doi: 10.1038/s41556-022-01042-3