Identified critical protein that promotes the progression of skin cancer in metastatic melanoma

Could you please introduce yourself and tell us a little bit about your professional history?
Carlton: As a Wellcome Trust Senior Research Fellow, I direct a lab at the Francis Crick Institute and King’s College London. My group employs microscopical, biochemical, and genetic methods to study how organelles—the internal structures of cells—are built and modified.

Sanz-Moreno: As a Senior Fellow for Cancer Research UK, I oversee a lab at the Queen Mary University of London’s Barts Cancer Institute. To comprehend how cancer cells spread throughout the body, my group combines “OMICs” technology, cell and molecular biology, 3-Dimensional biology, animal models, and patient data.

One of the three main kinds of skin cancer is melanoma. What distinguishing features do melanoma tumors have?
Melanocytes, the skin cells that produce the pigment (melanin), are where melanoma develops. More hazardous than the other types of skin cancer, melanoma is much less prevalent. Because melanoma has a strong propensity to spread throughout the body, this behavior is termed aggressive.

The main reason for cancer-related mortality is cancer metastasis or the spread of the disease. What is currently understood regarding melanoma spread, and what questions did this study seek to answer?

Melanoma is extremely deadly since it can grow and spread to numerous body organs, including the lymph nodes, skin, lungs, liver, brain, and bone. Melanoma cells must separate from the initial location, penetrate the nearby healthy tissue, and get entry to lymphatic and blood arteries in order to spread throughout the body.

The nucleus is a big, hard structure inside each cell that houses its genetic material but also limits the cell’s capacity to pass through the small openings in the tumor’s surroundings. For cancer cells to fit through these openings, their nucleus must be made more pliable. By creating lab-based procedures to examine the nucleus of melanoma cells, this study aimed to comprehend how the cells overcome these difficulties. These findings were subsequently verified in vivo in mouse and human tissues.

What were your primary findings and how did you go about doing your study?
During metastasis, cancer cells must fit through cracks and openings in tissues to colonize new locations. One of the main physical obstacles to this migration is the cancer cell’s nucleus, therefore metastasizing cancer cells must be skilled at squeezing their nucleus through these openings.

When comparing the metastases and original tumors of patients with their melanoma cells, we discovered that the latter had higher levels of the protein LAP1. We demonstrated that this protein localizes to the nuclear envelope—a membrane that envelops and encloses the nucleus—using microscopy techniques. We demonstrated that LAP1 localized to nuclear envelope protrusions that allowed the nucleus to shift shape using imaging of living cells.

We employed genetic methods to increase LAP1 levels in early melanoma cells and decrease LAP1 levels in metastatic melanoma cells. We discovered that cancer cells were more able to alter the structure of their nucleus and pass through openings the more LAP1 they had. We demonstrated that LAP1 levels were higher near the edges of melanomas developed in mouse and human patient tissues using immunohistochemistry.

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Additionally, we demonstrated that melanoma cells were better able to infiltrate collagen and the dermis when their levels of LAP1 were elevated. Finally, we discovered that LAP1 levels in human melanoma samples might be used as a prognostic readout of disease-free survival.

What potential effects on patient outcomes and future medicines could these discoveries have?

We believe that by concentrating on LAP1 and the factors that affect nuclear deformability, we may be able to stop cancer cells from slipping through cracks and spreading throughout the body. An additional strategy would involve focusing on the blobs or bulges inside the nucleus of metastatic cells.

What comes next for your research and you?
We want to investigate if we can inhibit the action of this protein to prevent metastasis as well as how other cells, such as immune cells, use LAP1 to enter malignancies.

Where can readers go to learn more?

Jeremy Carlton’s bio
Carlton is a Reader in Molecular Cell Biology at King’s College London and the Francis Crick Institute as well as a Wellcome Trust Senior Research Fellow.
His study primarily focuses on cell division, where he has identified processes that allow cells to complete cytokinesis and rebuild their nuclear envelope.

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Regarding Professor Victoria Sanz-Moreno

At the Barts Cancer Institute, Moreno holds the titles of Professor of Cancer Cell Biology and Senior Fellow for Cancer Research UK (Queen Mary University of London). The Society for Melanoma Research recently presented her with the Estela Medrano Memorial Award. Her research group is focused on figuring out how cancer cells spread, interact with their complicated environment, and react to current anti-cancer treatments.


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