Research by Queen Mary University of London, King’s College London and the Francis Crick Institute has 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 that allows cells to migrate and spread throughout the body.
The study, published today in Cell Biology Nature, modeled the behavior of aggressive melanoma cells capable of modifying the shape of their nucleus to overcome the physical constraints that cancer cells encounter when migrating through tissues. 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 a poor prognosis in melanoma patients.
Melanoma is a type of skin cancer that can spread to other organs in the body. The spread of cancer or “metastasis” is the leading cause of cancer-related death. While metastasis has been widely studied, the mechanisms by which it occurs are poorly understood. The study results shed new light on a mechanism of melanoma progression and might pave the way for the development of new ways to target the spread of melanoma.
The study
The study was co-led by Professor Victoria Sanz-Moreno of Queen Mary’s Barts Cancer Institute and Dr Jeremy Carlton of King’s College London and the Francis Crick Institute, and primarily funded by Cancer Research UK, the Wellcome Trust and the Barts Charity .
In the study, the team challenged aggressive and less aggressive melanoma cells in lab experiments to migrate through pores of an artificial membrane smaller than the size of their nucleus. The aggressive cells came from a site of metastasis in a patient with melanoma, and the less aggressive cells came from the original or “primary” melanoma tumor of the same patient.
To form metastases, cancer cells must break away from the primary tumour, travel to another part of the body and begin to grow there. However, the dense environment of a tumor makes this physically difficult for cancer cells.
Cells contain a large, rigid structure called the nucleus that stores the cell’s genetic information, but also limits a cell’s ability to move through the tight spaces of the tumor environment. For cancer cells to squeeze through these gaps, they need to make their core more malleable.
Imaging performed following the migration experiments showed that the aggressive cells were able to move more efficiently through the pores than the less aggressive ones by forming bulges at the edge of their nucleus called “bubbles”. Genetic analyzes of melanoma cells revealed that the aggressive cells that formed the bullae contained higher levels of the protein LAP1, which is found in the membrane that surrounds the nucleus (called the nuclear envelope).
Dr Jeremy Carlton, whose lab is interested in understanding the dynamics of membrane-bound structures in cells, said:
“The nuclear envelope is attached to the underlying nucleus, and our research shows that the LAP1 protein loosens this attachment, allowing the nuclear envelope to bulge and form bubbles that make the nucleus more fluid. As a result, cancer cells might squeeze through gaps that would normally stop them. »
When the team blocked the production of the protein LAP1 in the aggressive cells and challenged them to migrate through the pores in lab experiments, they found that the cells were less able to form bubbles of nuclear envelope and less able to squeeze through these gaps.
The team also observed the same expression pattern of LAP1 in melanoma patient samples. Levels of LAP1 were higher in tissue samples taken from sites of metastasis in patients with melanoma compared to levels found in primary tumors. Patients who had elevated levels of LAP1 in cells around the edge of the primary tumor had more aggressive cancer and poorer outcomes, suggesting that the protein might be used to identify subpopulations of melanoma patients who might have a higher risk of aggressive disease.
Professor Sanz-Moreno, whose research group is interested in understanding how cancer cells communicate with their environment to promote their growth and spread, said:
“Melanoma is the most aggressive and deadliest type of skin cancer. By combining the expertise of my lab with that of Dr. Carlton, we gained a new mechanistic understanding of how LAP1 contributes to melanoma progression, and showed that LAP1 is a key regulator of melanoma aggressiveness in laboratory and patient models.”
“Because LAP1 is expressed at such high levels in metastatic cells, interfering with this molecular machinery might have a large impact on the spread of cancer. There are currently no drugs that directly target LAP1. LAP1 and nuclear envelope blebbing to see if it is possible to block this mechanism of melanoma progression.”
The team would like to investigate whether LAP1-driven nuclear envelope blebbing occurs in other cells that compose and move around a tumor’s environment, such as immune cells, to determine if this process in other cells help or hinder cancer progression.
Dr Iain Foulkes, executive director of research and innovation at Cancer Research UK, which part-funded the study, said:
“Studies like this are a perfect example of why Cancer Research UK is passionate regarding funding research that furthers our knowledge of the effects of cancer on the biology of our bodies, in addition to research that focuses on what is happening in the clinic.
This new understanding of how the nucleus of a melanoma cell can become more fluid to move around the body is useful in strengthening our knowledge of how cancer works and opens a new avenue of investigation into ways to make more difficult for cancer to spread.
The study’s first author, Dr Yaiza Jung, carried out the work as part of her PhD funded by the Francis Crick Institute and King’s College London.
