Peculiar proteins allow cancer cells to change the shape of the nucleus and spread throughout the body!

Research led by Queen Mary University of London, King's College London and the Francis Crick Institute found a protein that makes melanoma, the most severe type of skin cancer, more aggressive by giving cancer cells the ability to change the shape of the nucleus, a trait that allows cells to migrate and spread
throughout the body.

The study, published in the journal Nature Cell Biology, mimics the behavior of aggressive melanoma cells, which are able to change the shape of the nucleus and overcome the physical limitations
cancer cells encounter as they migrate through tissues.
The study found that these aggressive melanoma cells contained a protein called LAP1, and elevated levels of this protein were associated with
poor prognosis for melanoma patients.

Melanoma is a type of skin cancer that can spread to other organs
in the body.
Cancer spread or "metastasis" is the leading cause
of cancer-related death.
Although metastasis has been extensively studied, the mechanism by which it occurs is unclear
.
The findings of this study provide new clues to the mechanism of melanoma development and may pave the way
for the development of new methods against the spread of melanoma.

Migration through the nucleus

The study, co-led by Professor Victoria Sanz-Moreno from Bartz Cancer Institute and Dr Jeremy Carlton from King's College London and the Francis Crick Institute, was funded
primarily by Cancer Research UK, Wellcome Trust and Bartz Charities.

In this study, the team experimentally challenged invasive and non-invasive melanoma cells to migrate
through pores on artificial membranes smaller than the size of the nucleus.
Aggressive cells come from the site of metastasis in one melanoma patient, while less aggressive cells come from primitive or "primary" melanoma
in the same patient.

In order to metastasize, cancer cells need to be isolated from the primary tumor, metastasized to another part of the body and begin to grow
there.
However, the dense environment surrounding the tumor makes it difficult for cancer cells to do this
physically.

The cell contains a large, rigid structure called the nucleus, which stores the cell's genetic information, but it also limits the cell's ability to
pass through tight gaps in the tumor environment.
In order for cancer cells to squeeze through these gaps, they need to make the nucleus more malleable
.

Imaging performed after migration experiments showed that aggressive cells were able to pass through the pores more efficiently than less aggressive cells because they formed bumps called "blebs" at the edge of the nucleus
.
Genetic analysis of melanoma cells revealed that the aggressive cells that form the vesicles contain higher levels of the LAP1 protein, which is located within
the membrane that surrounds the nucleus, called the nuclear membrane.

Dr.
Jeremy Carlton's lab is interested in understanding the dynamics of endomembrane-binding structures, saying:

"The nuclear membrane is tethered to the nucleus below, and our study shows that the LAP1 protein loosens this bondage, causing the nuclear membrane to bulge and form bubbles, making the nucleus more mobile
.
" As a result, cancer cells can squeeze through the gaps
that normally block them.
”

When the team experimentally blocked the production of the LAP1 protein in aggressive cells before sending cancer cells through the pores, they found that the cells were less able to form nuclear vesicles and had a harder time squeezing through these gaps
.

The team also observed the same pattern of LAP1 expression in melanoma samples from patients
.
Tissue samples taken from metastatic sites in melanoma patients have higher
levels of LAP1 compared to the primary tumor.
Patients with high levels of LAP1 in cells at the edge of the primary tumor had stronger aggressive cancers and worse outcomes, suggesting that the protein could be used to identify subsets
of melanoma patients who may have a higher risk of aggressive disease.

Prof.
Sanz-Moreno's research group is interested in understanding how cancer cells communicate with the environment to promote their growth and spread, saying:

Melanoma is the most aggressive and deadly type
of skin cancer.
By combining my lab and Dr.
Carlton's expertise, we gained a new mechanistic understanding of how LAP1 promotes melanoma progression and demonstrated in laboratory and patient models that LAP1 is a key regulator of melanoma aggressiveness
.
”

"Because LAP1 is expressed so high in metastatic cells, interfering with this molecular mechanism could have a significant impact
on cancer spread.
" There are currently no drugs that directly target LAP1, so going forward, we hope to investigate ways to target LAP1 and nuclear vesicles to see if it is possible to stop the mechanism
by which melanoma develops.
”

The team hopes to investigate whether LAP1-driven blistering of the nuclear membrane occurs in other cells that make up and travel through the tumor environment, such as immune cells, to determine whether this process in other cells contributes to or hinders cancer progression
.

Dr Iain Foulkes, Executive Director of Research and Innovation at Cancer Research UK, which provided part of the funding for the research, said:

"Research like this is a great example of why Cancer Research UK is keen to fund research that goes beyond clinical research to further understand the impact of
cancer on our body biology.
"

This new understanding of how melanoma nuclei become more mobile and able to move through the body helps build our understanding of how cancer works and opens up new avenues
for studying how to make cancer harder to spread.
”

Journal Reference:

1. Jung-Garcia, Y.
   , Maiques, O.
   , Monger, J.
   et al.
   LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion.
   Nat Cell Biol, 2023 DOI: 10.
   1038/s41556-022-01042-3