A key protein that helps melanoma spread has been identified

In this interview, News-Medical speaks with Dr. Jeremy Carlton and Professor Victoria Sanz Moreno about their latest research on the spread of skin cancer.

Please, could you introduce yourself and tell us about your professional background?

Carlton: I am a Senior Research Fellow at the Wellcome Trust, and run a laboratory at King’s College London and the Francis Crick Institute. My lab uses microscopic, biochemical, and genetic techniques to investigate how cells assemble and remodel their inner compartments called organelles.

Sans Moreno: I’m a Senior Fellow at Cancer Research UK, and run a lab at the Barts Cancer Institute, Queen Mary University of London. My lab combines OMICs, cell biology, molecular biology, 3D biology, mouse models and patient samples to understand how cancer cells become metastatic.

Skin cancer is one of the three main types of skin cancer. What are the main characteristics of skin cancer?

Skin cancer arises from melanocytes, the pigment (melanin)-producing cells in the skin. Melanoma is less common than other types of skin cancer but is much more serious. The reason behind his aggressive behavior is that melanoma has a great tendency to spread throughout the body.

Image credit: LightField Studios / Shutterstock.com

Image credit: LightField Studios / Shutterstock.com

Cancer spread or ‘metastases’ is the leading cause of cancer-related deaths. What is currently known about the prevalence of skin cancer, and what did this study aim to investigate?

Melanoma can spread and grow in many organs of the body (lymph nodes, skin, lungs, liver, brain, and bones), which is why it is so dangerous. To spread, melanoma cells need to break away from the primary site and invade surrounding healthy tissue, then reach blood and lymphatic vessels to spread throughout the body.

Cells contain a large, rigid structure called the nucleus that stores the cell’s genetic information but also restricts the cell’s ability to move through narrow gaps in the tumor environment. Cancer cells need to make their nuclei more flexible in order to be able to squeeze through these vacuoles. This study sought to understand how melanoma cells overcome these challenges by designing laboratory experiments to image their nuclei. These observations were later confirmed in vivo in mice and human tissues.

How did you conduct your study, and what were your main findings?

Cancer cells need to squeeze through the cavities and holes in the tissues during metastasis to colonize new sites. The nucleus of the cancer cell is one of the main physical barriers to this migration, and metastatic cancer cells must be adept at squeezing their nuclei through these vacuoles.

We looked for differences between melanoma cells from patients’ metastases and their primary tumors and found that metastatic melanoma cells express more of a protein called LAP1. We used microscopic techniques to demonstrate that this protein is localized to the nuclear envelope, which is a membrane that encloses and surrounds the nucleus. Through live cell imaging, we showed that LAP1 was localized to bulges in the nuclear envelope allowing the nucleus to change its shape.

Image credit: Nemes Laszlo / Shutterstock.com

Image credit: Nemes Laszlo / Shutterstock.com

We used genetic approaches to decrease LAP1 levels in metastatic melanoma cells and raise LAP1 levels in primary melanoma cells. We found that the more LAP1 tumor cells had, the better they were able to change the shape of their nuclei and migrate through the vacuoles. We used immunohistochemistry to show that LAP1 levels were highest at the edge Melanomas grown in rat and human tissues.

We also showed that higher levels of LAP1 in melanoma cells made them more able to invade collagen and into the dermis. Finally, we found that in human melanoma samples, LAP1 levels can be used as a read-out for disease-free survival.

How might these findings affect future treatments and patient outcomes?

We believe that by targeting LAP1 and the mechanisms that influence nuclear deformation, we may be able to prevent cancer cells from squeezing through the vacuoles and spreading. Alternatively, targeting the bulges or blebs in the nuclei of metastatic cells could be an alternative method.

What’s next for you and your research?

We would now like to see how other cells – such as immune cells – use LAP1 to allow its infiltration into tumors but also to explore whether we can reduce malignancy by blocking the function of this protein.

Where can readers get more information?

About Dr. Jeremy Carlton

Carleton is Reader in Molecular Cell Biology and Senior Research Fellow at the Wellcome Trust at King’s College London and the Francis Crick Institute.His research mainly focuses on cell division, as he explored the mechanisms by which cells complete cytokinesis and renew their nuclear envelope during the process of cell division.

About Professor Victoria Sanz Moreno

Sanz Moreno is Professor of Cancer Cell Biology and Cancer Research UK and Senior Fellow at the Barts Cancer Institute (Queen Mary University of London). She recently received the Estela Medrano Memorial Award from the Skin Cancer Research Society. Her lab is interested in understanding how cancer cells become metastatic, interact with the complex environment around them, and respond to current anti-cancer therapies.

Yaiza Jung Garcia was a Class C.PhD student Rick King was jointly supervised by Carlton and Sanz Moreno. She now works for the NHS Lothian.

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