The most dangerous form of skin cancer, known as melanoma, has been found to be driven by a protein discovered by researchers at Queen Mary University of London, King’s College London, and the Francis Crick Institute. This protein gives the cancer cells the ability to change the shape of their nucleus, which enhances their migration and spread throughout the body.
Skin cancer cells encounter physical barriers during their migration through tissues, and this study published today in Nature Cell Biology models the behavior of aggressive melanoma cells that can alter the shape of their nucleus to avoid these barriers. High quantities of a protein called LAP1 were detected in these aggressive melanoma cells, and the researchers found that this protein was associated with a poor prognosis for melanoma patients.
The skin cancer melanoma can metastasize to other parts of the body. Metastasis, or the spread of cancer, is the primary cause of mortality for those with the disease. Despite a large amount of research, our understanding of what actually triggers metastasis remains limited. The study’s results provide new insight into a process of melanoma progression and may result in the development of new methods of preventing the spread of the disease.
Queen Mary’s Barts Cancer Institute Professor Victoria Sanz-Moreno and King’s College London and Francis Crick Institute’s Dr. Jeremy Carlton co-directed the study.
Researchers in this study tested the ability of aggressive and less aggressive melanoma cells to navigate gaps in an artificial membrane smaller in diameter than the cancer cells’ nuclei. The more aggressive cells originated from a patient’s metastatic site, while the less aggressive cells originated from the patient’s primary melanoma tumor.
Metastasis occurs when cancer cells leave the initial tumor and spread to a new location to begin a new tumor. However, the cramped conditions inside a tumor prevent them from doing so.
The nucleus of a cell is a big, rigid structure that contains the cell’s genetic information but also hinders the cell’s ability to travel through the narrow gaps of the tumor’s surroundings. A more flexible nucleus is required if cancer cells are to squeeze through these openings.
After the migration studies, imaging revealed that the aggressive cells passed through the gaps with higher efficiency than the less aggressive cells because they had formed blebs at the edge of their nucleus. According to genetic tests of the melanoma cells, the LAP1 protein, which is located in the membrane that surrounds the nucleus, was found in greater abundance in the aggressive cells that generated the blebs.
Dr. Jeremy Carlton, whose team is interested in the dynamics of membrane-bound structures within cells revealed that the LAP1 protein loosens the tethering of nuclear envelope to its nucleus, allowing the nuclear envelope to bulge away and develop blebs that make the nucleus more fluid. So, the cancer cells were able to pass through narrow openings that would have otherwise prevented their spread.
By inhibiting LAP1 protein production, the research team observed that aggressive cells were less able to generate nuclear envelope blebs and less able to squeeze through these gaps when re-challenged to move through pores in laboratory experiments.
The group also saw this LAP1 expression pattern in patient samples of melanoma. The LAP1 levels in melanoma metastatic tissue samples were significantly greater than those in primary tumor tissue samples. Patients with high levels of LAP1 in the cells surrounding the edge of the original tumor had more aggressive cancer and poorer outcomes, suggesting that the protein could be utilized to identify subpopulations of melanoma patients who may be at increased risk of aggressive cancer.
Professor Sanz-Moreno, whose team studies how cancerous tumors utilize environmental cues to multiply and metastasize, said that melanoma is the most aggressive and fatal type of skin cancer. Their laboratory and Dr. Carlton’s have collaborated to uncover new mechanistic insights into LAP1’s role in melanoma progression and to demonstrate that LAP1 is a crucial regulator of melanoma aggressiveness.
Interfering with this molecular mechanism could have a significant effect on cancer metastasis because LAP1 is expressed at high levels in metastatic cells. Since there are no currently available medications that target LAP1, the researchers hope to conduct further research into methods of targeting LAP1 and nuclear envelope blebbing to determine whether or not they can inhibit this progression pathway in melanoma.
The group is interested in learning whether LAP1-driven nuclear envelope blebbing occurs in other cells that contribute to and migrate through a tumor’s environment, such as immune cells, and whether this activity aids or inhibits cancer progression.
According to Dr. Iain Foulkes, Cancer Research UK’s Executive Director of Research and Innovation, studies such as this one are a perfect example of research that deepens the knowledge of what cancer does to the biology of our bodies.
This new knowledge of how the nucleus of a melanoma cell can become more fluid to migrate across the body is valuable for developing the knowledge of how cancer behaves and opens a new path of exploration into strategies to make it harder to spread.
Sources:
Jung-Garcia, Y., Maiques, O., Monger, J. et al. LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion. Nat Cell Biol (2023). https://doi.org/10.1038/s41556-022-01042-3
