Researchers discover a protein that makes melanoma more aggressive.

Research led to melanoma by the Queen Mary University of London, King’s College London and the Francis Crick Institute has identified a protein that makes melanoma, the deadliest form of skin cancer, cancer cells more aggressive by giving them the ability to change the shape of their nuclei – a feature that allows cells to migrate and Allows it to spread around the body.

The study, published today in Nature Cell Biology, models the behavior of aggressive melanoma cells that are able to change the shape of their nuclei to overcome the physical limitations that cancer cells face when they migrate through tissues. The study found that these aggressive melanoma cells harbor high levels of a protein called LAP1 and that increased levels of this protein were associated with a poor prognosis in melanoma patients.

Melanoma is a type of skin cancer that can spread to other parts of the body. Cancer spread or ‘metastasis’ is the leading cause of cancer death. Although metastasis has been extensively studied, the mechanisms by which it occurs are poorly understood. The study results shed new light on the mechanism of melanoma progression and may pave the way for the development of new ways to target melanoma proliferation.

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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 was 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 laboratory experiments to migrate through pores in an artificial membrane smaller than the size of their nuclei. Aggressive cells were from the site of metastasis in a patient with melanoma and less-aggressive cells were from the original or ‘primary’ melanoma tumor in the same patient.

To metastasize, cancer cells must move away from the primary tumor, travel to another part of the body, and grow there. However, the dense environment of a tumor makes it physically difficult for cancer cells.

Cells have a large, rigid structure called a nucleus that stores the cell’s genetic information, but it also limits a cell’s ability to move through the tight gaps in the tumor environment. In order for cancer cells to squeeze through this gap, they have to make their nuclei more flexible.

Imaging conducted after the migration experiment showed that the aggressive cells were able to move more efficiently through the pores than the less-aggressive cells by forming bumps called ‘blebs’ at the edges of their nuclei. Genetic analysis of melanoma cells showed that aggressive cells that form blebs have high levels of the LAP1 protein, which resides in the membrane that surrounds the nucleus (called the nuclear envelope).

Dr. Jeremy Carlton, whose laboratory is interested in understanding the dynamics of membrane-bound structures within cells, said:

“The nuclear envelope is attached to the underlying nucleus, and our investigation shows that the LAP1 protein relaxes this tethering, causing the nuclear envelope to swell and make the nucleus more fluid. The gap that would normally stop them.”

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When the team blocked the production of the LAP1 protein in invasive cells and re-challenged them to migrate through the pores in laboratory experiments, they found that the cells were less able to form nuclear envelope blebs and less able to push through these gaps.

The team also observed a similar 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 levels found in the primary tumor. Patients who had high levels of LAP1 in 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 who may be at higher risk of invasive disease.

Professor Sanz-Moreno, whose research group is interested in understanding how cancer cells interact with their environment to promote their growth and spread, said:

“Melanoma is the most aggressive and lethal type of skin cancer. By combining Dr. Carlton’s expertise with my laboratory, we gained a new mechanistic understanding of how LAP1 contributes to melanoma progression and demonstrated that LAP1 is a key regulator. Melanoma invasiveness in laboratory and patient models .”

“Because LAP1 is expressed at such high levels in metastatic cells, interfering with this molecular machinery can have a major impact on cancer spread. There are currently no drugs that directly target LAP1, so the search.

The 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.

Dr Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, which partly funded the study, said:

“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.

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.”

The first author of the study, Dr Yaiza Jung, conducted the work as part of her PhD funded by The Francis Crick Institute and King’s College London.