ICRF Research Investigates Role of Melanosomes and Lymphatic Vessels in the Spread of Skin Cancer

Malignant melanoma is the deadliest form of skin cancer – so aggressive that it can spread to other parts of the body even in very early stages. How? Dr. Shoshana Greenberger of the Chaim Sheba Medical Center and recipient of an ICRF Project Grant is looking at the unique role of melanosomes, the cells that produce and store pigment, and how to keep them from carrying the melanoma into the lymphatic system. 

How does skin cancer get into the lymphatic system to spread to other parts of the body? 

My research is about malignant melanoma. This is the deadliest skin tumor, and we know that malignant melanoma cells can enter the lymphatic system even in the very early stages of the tumor. Even if it’s one or two millimeters deep, it can enter and metastasize into the lymphatic system. When it metastasizes in the lymphatic system, the next step is to get into the blood system and send metastases to distant sites. This is the reason why people actually die from melanoma. 

We were curious about how a melanoma tumor can cause lymphatic vessels to grow up around it. (Lymphatic vessels are a network of microvessels that move lymphatic fluid and white blood cells throughout the lymphatic system. Lymphatic vessels are found in all tissues except for bone marrow and the central nervous system.) Everyone has a lymphatic system; this is very important for our health. We also have lymphatic vessels within our skin, but we know that in melanoma, we see many more lymphatic vessels around a tumor, even in the very early phases of melanoma. This is very important for the metastasis into the lymphatic system. 

We wanted to know how that happened. There is a very important protein called VEGF-C that is secreted by melanoma cells, but this was not enough to understand the whole process. We thought that maybe a melanoma could secrete vesicles (blisters) that affect the lymphatic system. We know that melanoma is made of melanocytes (the cells in our body that make melanin).  

Melanoma can secrete melanosomes, which are vesicles. Our hypothesis was that melanoma, through the secretion of melanosomes, can affect the growth of the lymphatic vessels. What we found is that melanoma cells, even in the very early phases of melanoma progression, secrete melanosomes that can enter the cells of the lymphatic system, and they don’t only enter the system; they can also affect it. We see that the lymphatic system, the lymphatic cells, when they take up the melanosomes, become more active. They make more vessels. They migrate more. They are much more active, and they secrete many more proteins that are important for the creation of more lymphatic vessels. We think that this is a very important mechanism by which melanoma can affect its microenvironment, the environment of the tumor. 

In melanoma, we see many more lymphatic vessels around a tumor, even in the very early phases of melanoma. This is very important for the metastasis into the lymphatic system. We wanted to know how that happened.

Dr. Greenberger

What are your hopes for your research? 

We have already shown in our past research that melanosomes can affect other cells in the tumor vicinity (This was a research done by Carmit Levy’s lab, with the help of the ICRF), and this was the first time that we showed the effect on cells of the lymphatic system. This was our first and very important work about lymph angiogenesis, the creation of lymphatic cells, and our next step is to understand how the melanosomes can affect not only the growth of the lymphatic system but also the immune reaction that happens in the vicinity of the tumor and, very importantly, in the lymphatic system because we know the future of melanoma treatment is probably in immunotherapy. 

Immunotherapy means that we try to activate a patient’s own immune system against the tumor. We know that cells in the environment of the tumors have many mechanisms to down-regulate and silence the immune system, and this is probably one of the reasons why melanoma can escape the immune system. So now we work not only on the effect of melanoma on the growth of the lymphatic system but also on how the melanosomes affect the immune system in the lymphatic vessels and other cells in the environment of the tumor. We think this is very important because if we can understand the mechanism by which the cells in the vicinity are affected by melanosomes, maybe we can intervene and prevent the progression of the melanoma to the lymphatic system and then to the distant metastases.  

What has ICRF funding allowed you to accomplish in your research and in your career? 

ICRF funding was very important for my career. This is the second time I received an ICRF grant, and as a physician, it’s very hard to establish a lab and grow the lab because, as an MD-PhD, as a physician-scientist, you always have to balance your work and responsibilities. I believe very much in the role of physician-scientists because we are in close contact with the patients. We can see the real clinical questions and we can take them back to the lab and work on them. Not only that, but we can also work on human specimens, not only on mice and cells that were grown in the lab for generations and are very far away from the real tumors. 

It is very important to me to be a scientist and to also be a physician. This is a great challenge, and the grants I received from ICRF really helped me in establishing my lab and funding my research, even in the first phases when I came back from the postdoc in Boston in 2010 and established my lab, and even now, in the last year, when my lab grew and I could get more students and postdocs and manage my lab.