A protein that helps lethal skin cancer spread through the body has been identified, according to scientists, offering a new hope for cancer treatment. Protein LAP1 allows cancer cells to become more aggressive by letting them change the shape of their nucleus and migrate around the body.
The most serious type of cancer cells, melanoma, were found to harbour LAP1 and high levels of it were linked to poor prognosis. The protein facilitates cancer spread, or metastasis, which is the leading cause of cancer-related deaths.
Metastasis has been extensively studied but so far little is known about how it works. The research could offer a new pathway to developing ways to target the spread of melanoma, including never-before-seen drugs to target LAP1 and using the presence of the protein to identify patients at risk of aggressive disease.
To investigate how it operates, Queen Mary University of London, King’s College London, and the Francis Crick Institute researchers modelled the behaviour of aggressive melanoma cells. To metastasise, cancer cells have to break away from the primary tumour, migrate to a new part of the body and start growing there.
However, tumour cells contain a large stiff structure known as the nucleus, which stores its genetic information but also restricts the tumour’s ability to move through tight gaps in surrounding tissue. Melanoma cells can change their nuclei shape and overcome the physical constraints cancer cells encounter moving through tissues, possibly moving to other organs in the body - scientists discovered LAP1 made this possible.
In order to squeeze through the gaps they have to make their nucleus more malleable. In laboratory experiments the team challenged aggressive and less-aggressive melanoma cells to migrate through pores in an artificial membrane, smaller than their nucleus.
The aggressive cells were taken from an area of metastasis in a patient with melanoma, while less-aggressive ones were from the original melanoma tumour in the same patient. Images taken after the migration experiments showed aggressive cells could move through pores more efficiently than less-aggressive ones.
To do so the cells formed bulges at the edge of their nucleus, called “blebs.” Blebs contain high levels of LAP1 protein, which inhabits the membrane surrounding the nucleus, known as the nuclear envelope.
By blocking LAP1 from being produced and challenging them to try and migrate through the pores again, the team showed cells had a harder time forming blebs and squeezing through the gaps. The team found LAP1 levels were higher in tissue samples taken from metastasis sites, versus primary tumours, and those with more of the protein in their cells had more aggressive cancer with poorer outcomes.
Professor Sanz-Moreno, the study co-lead from Queen Mary’s Barts Cancer Institute, said: “Melanoma is the most aggressive and deadly type of skin cancer. We have gained 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.
“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.”
Dr Jeremy Carlton, from King’s College London and The Francis Crick Institute, described how blebs let the cancer move through the body. He said: “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. As a result, the cancer cells could squeeze through gaps that would normally stop them.”
Next, the team writing in Nature Cell Biology would like to investigate whether nuclear envelope blebbing by LAP1 occurs in other cells, such as immune cells. Doing so could determine whether the process in other cells helps or hinders cancer’s progression.
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.”
