Melanoma is a type of skin cancer that can spread to other organs in the body. While metastasis has been extensively studied, the mechanisms by which it occurs are not fully understood. Now, research led by Queen Mary University of London, King’s College London, and the Francis Crick Institute has identified a protein that makes melanoma more aggressive by giving cancer cells the ability to change the shape of their nucleus.
The study, “LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion,” is published in Nature Cell Biology. The study found that 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.
The study was co-led by Victoria Sanz-Moreno, PhD, professor, cancer cell biology at Queen Mary’s Barts Cancer Institute and Jeremy Carlton, PhD, reader in molecular and cellular biology at King’s College London and 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 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,” explained Carlton. “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 observed that the cells were less able to form nuclear envelope blebs and less able to squeeze through these gaps.
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.
The findings from the study shed new light on a mechanism of melanoma progression and may pave lead to the development of new ways to target melanoma spread.
