Studies led by researchers at Queen Mary University of London, King's College London, and the Francis Crick Institute have identified a protein that makes melanoma, the most serious type of skin cancer, more aggressive by giving cancer cells the ability to change the shape of their nucleus-a characteristic which allows the cells to migrate and spread around the body.
The research, published in Nature Cell Biology, modeled the behavior of aggressive melanoma cells that are able to change the shape of their nucleus to overcome the physical constraints that cancer cells encounter when they migrate through tissues (2023; doi: 10.1038/s41556-022-01042-3). The study found that these aggressive melanoma cells harbored high levels of a protein called LAP1 and that increased levels of this protein were linked to poor prognosis in melanoma patients.
While metastasis has been extensively studied, the mechanisms by which it occurs are poorly understood. The findings from the study shed new light on a mechanism of melanoma progression and could pave the way for the development of new ways to target melanoma spread.
Study Details
The research was co-led by Victoria Sanz-Moreno, PhD, Professor of Cancer Cell Biology at Queen Mary's Barts Cancer Institute, and Jeremy Carlton, PhD, Senior Research Fellow at the Francis Crick Institute. In the study, the team challenged aggressive and less-aggressive melanoma cells in laboratory experiments to migrate through pores in an artificial membrane that were smaller than the size of their nucleus. The aggressive cells were from a site of metastasis in a patient with melanoma, and the less-aggressive cells were from the original or primary melanoma tumor of the same patient.
Imaging conducted after the migration experiments showed that the aggressive cells were able to move through the pores more effectively than the less-aggressive ones by forming bulges at the edge of their nucleus called blebs. Genetic analyses of the melanoma cells revealed that the aggressive cells that formed the blebs contained higher levels of the LAP1 protein, which sits within the membrane that surrounds the nucleus, known as the nuclear envelope.
"The nuclear envelope is tethered to the underlying nucleus, and our investigations show that the LAP1 protein loosens this tethering, allowing the nuclear envelope to bulge away and form blebs that make the nucleus more fluid," Carlton noted. "As a result, the cancer cells could squeeze through gaps that would normally stop them."
When the team blocked the production of the LAP1 protein in aggressive cells and re-challenged them to migrate through pores in laboratory experiments, they found that the cells were less able to form nuclear envelope blebs and less able to squeeze through these gaps.
The team also observed the same pattern of LAP1 expression in melanoma samples from patients. LAP1 levels were higher in tissue samples taken from sites of metastasis in melanoma patients compared to the levels found in primary tumors. The patients who had high levels of LAP1 in the cells around the edge of the primary tumor had more aggressive cancer and poorer outcomes, suggesting that the protein could be used to identify subpopulations of melanoma patients that may be at higher risk of aggressive disease.
"Melanoma is the most aggressive and deadly type of skin cancer. By combining the expertise of my laboratory with that of Dr. Carlton's, we have gained a new mechanistic understanding of how LAP1 contributes to melanoma progression, and have shown that LAP1 is a key regulator of melanoma aggressiveness in laboratory and patient models," Sanz-Moreno noted. "Because LAP1 is expressed in such high levels in metastatic cells, interfering with this molecular machinery could have a big impact on cancer spread. There are currently no drugs that target LAP1 directly, so looking to the future we would like to investigate ways to target LAP1 and nuclear envelope blebbing to see if it is possible to block this mechanism of melanoma progression."
The research team would like to investigate whether nuclear envelope blebbing driven by LAP1 occurs in other cells that make up and move through a tumor's environment, such as immune cells, to determine if this process in other cells helps or hinders the progression of cancer.
"Studies like this one are a perfect example of why Cancer Research UK is passionate about funding research that furthers our knowledge of what cancer does to the biology of our bodies, in addition to research that focuses on what's happening in the clinic," noted Iain Foulkes, PhD, Executive Director of Research and Innovation at Cancer Research UK. "This new understanding of how the nucleus of a melanoma cell can become more fluid to move around the body is useful for building our knowledge of how cancer works and opens up a new avenue of investigation into ways to make it harder for cancer to spread."