Role of the Immune Microenvironment in Melanoma Bone Metastasis

Why This Research Matters
Cancer metastasis happens when cancer cells spread from where they start to other parts of the body. In melanoma (a deadly form of skin cancer), these cancer cells can travel to many parts of the body including brain, liver, and lung. These cells can also arrive to the bone, which can lead to devastating consequences including bone pain and fractures. Sadly, it is difficult to treat patients who discover melanoma cells in the bone, since these cells do not respond well to common treatments compared to patients who have melanoma cells in other parts of the body. It is still unknown why this happens, because up until now there have been very few mouse models that resemble these clinical features, which made it difficult to understand; 1) why these cancer cells arrive in the bone, and 2) how these melanoma cells in the bone do not respond to therapies.

What We Are Studying
In our lab, we developed mouse models that show melanoma cancer cells arriving to the bone and other organs, which is what commonly occurs in melanoma patients. From here we used a technique called scRNAseq to see what individual cells in the bones of tumor mice look like compared to bones from healthy mice.

How the Study Works
We discovered that different types of neutrophils, which are cells that serve as the first attackers against infection and diseases, are expressed in higher numbers in bones of tumor mice compared to healthy mice. We also saw that B cells, a population of immune cells that produce factors that fight bacteria and infections, were reduced in bones of tumor mice versus healthy mice. When we targeted undeveloped neutrophils with therapies, we saw fewer melanoma cancer cells in the bone and liver. However, when we targeted more mature neutrophils we saw the opposite effect, in fact we saw more tumor cells present in the bones and other organs including liver and kidneys. This revealed to us that different cell populations can contribute to the presence of melanoma cells in the bone. That is why it is important to understand how to better target these neutrophils and B cells so that we can prevent these melanoma cells from arriving to the bone. To investigate this further, we will be using specially bred mice that lack these neutrophils and B cells to determine whether the lack of these cells prevent melanoma cancer cells from arriving to the bone. It will also show how melanoma cells change the bone environment, including how they modify the immune system, to become resistant to therapies.

Expected Impact
Results arising from these studies will reveal strategies to prevent melanoma cells from arriving to the bone in patients, which will lead to better quality of life and improve response to treatment.