• Researchers studied melanoma tumor cells to better understand how these cells are able to migrate through physically dense tissues and spread throughout the body.
• They discovered a nuclear membrane protein called LAP1 that enables melanoma cells to change the shape of their large and stiff nucleus, thus permitting the tumor cell to migrate through confined spaces.
• Since levels of the LAP1 protein are correlated with melanoma survival rates, LAP1 could potentially be used as a prognostic marker in melanoma patients.

Melanoma is a type of skin cancer that accounts for around 5% of all skin cancers but causes at least 75% of skin cancer deaths.

The reason why melanoma is so dangerous is the ability of melanoma cells to migrate to and thrive in the brain, lungs, and other major organs. When melanoma cells from the original tumor spread to other parts of the body and form a new tumor, the melanoma is metastatic.

Research has shown that to migrate through tissues tumor cells must overcome physical constraints.

One major obstacle to cell migration is the cell nucleus, which occupies a large fraction of the cell volume and is normally less malleable than the surrounding cytoplasm. The mechanism whereby cells overcome these physical challenges is unclear.

Now, researchers at Queen Mary University of London, King’s College London and the Francis Crick Institute have identified a protein – LAP1 – that enables melanoma cells to change the shape of the nucleus and thus allow cell migration.

“The work is very nice and clearly shows the important role of increased LAP1 expression in promoting cancer metastasis and cancer cell invasion,” Jan Lammerding, Ph.D., professor at the Meinig School of Biomedical Engineering and the Weill Institute for Cell and Molecular Biology at Cornell University, not involved in the study, told Medical News Today.

The study was recently published in Nature Cell Biology.

Role of the cell nucleus in tumor cell migration

The cell nucleus, which stores DNA, is enclosed by a double-layered membrane called the nuclear membrane or nuclear envelope.

Previous research has shown that in response to cell migration through confined spaces, the nuclear membrane can partially detach from the underlying nuclear lamina, which is a dense mesh of proteins that lines the inside of the nuclear membrane. This results in the formation of a “bleb,” which is an irregular bulge in the nuclear membrane.”

For the study, the researchers obtained two cell lines from a single melanoma patient:

The researchers then conducted an experiment to visualize how the two cell types migrate through a matrix of collagen fibers, which mimics the extracellular matrix (the material that surrounds cells in living tissue).

When the researchers viewed the cells following the migration experiments, they observed that 30% of the metastatic lesion (aggressive) melanoma cells displayed NE blebs compared with only 5% of the primary tumor (less aggressive) melanoma cells.

LAP1 supports nuclear envelope ‘blebbing’

In genetic analyses of the melanoma cells, the researchers observed that the degree of nuclear membrane blebbing, as well as the migratory and invasive abilities of melanoma cells, were positively correlated with the levels of LAP1 nuclear membrane protein. This suggests that the LAP1 protein enables constrained migration and invasion.

Human cells express two isoforms (or variants) of the LAP1 protein: LAP1B (the long isoform) & LAP1C (the short isoform).

Using in vitro and in vivo models of human melanoma progression, the researchers found that the LAP1C isoform supports nuclear membrane blebbing, constrained migration, and invasion by allowing a weaker coupling between the nuclear membrane and the underlying network of the nuclear lamina (fibers).

LAP1 levels are also associated with disease prognosis.

The researchers found that high levels of the LAP1 protein in the tumor invasive front (the tumor-host interface) were associated with shorter disease-free survival, suggesting that higher LAP1 levels are linked to worse disease prognosis. This means that LAP1 could be used as a prognostic marker in melanoma patients.

In Dr. Lammerding’s opinion, this study could impact the clinical approach to patients with melanoma.

“In the short term, the discovery could lead to better treatment selection of melanoma patients, i.e., prescribing more aggressive treatments or more frequent surveillance to patients with high levels of LAP1 expression, as their cancers are more likely to metastasize.”

– Jan Lammerding, Ph.D., professor of biomedical engineering

Other implications for LAP1

Victoria Sanz-Moreno, Ph.D., study co-author and professor of cancer cell biology at Queen Mary University of London, told MNT:

“We think that by targeting LAP1 and mechanisms that influence nuclear deformability, we may be able to prevent cancer cells [from]squeezing through gaps and metastasizing. […] targeting the bulges or blebs in the nucleus of metastatic cells could be an alternative approach.”

In the study paper, the researchers express their hope this finding may guide research on healthy or pathological cells characterized by perturbed nuclear membranes.

Dr. Lammerding added that over time, “it may be possible to identify or develop drugs that reduce the expression of LAP1 in melanoma cells, or that shift the expression from LAP1C to LAP1B, which does not seem to promote cancer cell invasion and tumor growth (but could potentially affect other pro-metastatic functions).”

Robert A. Weinberg, Ph.D., professor of biology at Massachusetts Institute of Technology (MIT) and director of MIT Ludwig Center for Molecular Oncology, told MNT:

“This is an interesting finding. However, it is really a stretch to assume that this discovery will lead the way to new types of therapy. Instead, it is likely that the observed changes are one of dozens of downstream responses when cancer cells become aggressive and malignant.”

Limitations of the study and next steps

Dr. Weinberg pointed out “the limited number of cells studied and the apparent absence of strong data arguing that this change is actually causally important in enabling malignant progression” as the main limitations of the study.

Dr. Lammerding identified a few questions that were not addressed in the study and merit further research.

Since metastasis includes many other steps besides cancer cell invasion, he said “it remains to be seen whether LAP1C (and potentially also LAP1B, which is also increased in the metastatic cell lines) may alter additional cellular functions that promote metastatic progression.”

“The authors show that LAP1C expression promotes nuclear blebbing and also improves cancer cell migration through tight spaces, but they do not show that the nuclear blebbing itself is the mechanism that allows for better migration. Thus, it is possible that LAP1C expression has additional […] effects on cells that are responsible for the increased migration, such as changing the overall deformability of the cell nucleus, altering nucleo-cytoskeletal coupling, or modulating cell contractility or cell adhesion.”

– Dr. Jan Lamerding, professor of biomedical engineering

Dr. Sanz-Moreno noted that presently, “there are no drugs that block LAP1 function, so in [the] future, it will be interesting to design such therapies.”

She added that future research will focus on “how other cells, such as immune cells, use LAP1 to allow their infiltration into tumors.”

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