Midkine promotes uveal melanoma progression by stimulating ABCB5+ cancer stem cells

• Applicant: Dr. Margarete Karg
• Subject Area: Ophthalmology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445807620

While cancer within the eye is relatively rare, uveal melanoma is by far the most common. It is caused by the malignant transformation of melanocytes residing in the uveal tract of the eye. When these tumors develop, a number of treatments can successfully stop their growth and, in many cases, preserve functional vision. However, if tumor cells enter blood vessels and leave the eye, they can spread to other parts of the body and develop secondary tumors called “metastases”. This occurs in about 50% of the patients and, unfortunately, there is no successful treatment. Evidence suggests that tumor cells leave the eye early, possibly even before the doctor first diagnoses the patient with cancer. Two aspects of metastases derived from uveal melanoma are unusual: (i) they almost always develop in the liver, and (ii) there can be a delay of many years before they develop.The ultimate goal of this research is to develop new treatment methods for patients with liver metastases. In order to achieve this goal, we need to understand how the tumor cells leave the eye, enter the blood vessels, and then form tumors in the liver. We are developing a new animal model allowing us to track the movement of tumor cells within the body. We are using a highly sensitive imaging instrument that can “see” tumor cells within the eye, blood vessels, and liver. This was achieved by genetically modifying the tumor cells so they express a marker that can be seen by the instrument. This model system will allow us to study what causes the cells to leave the eye, move into the blood, and ultimately migrate into the liver.Based upon our past research, we hypothesize there are two important events that must occur in order for liver tumors to develop. The first event is that a small subset of tumor cells is established that are called “tumor initiating cells”. Even though all tumor cells proliferate, only the subset of “tumor initiating cells” can do so indefinitely and possess the ability to form new tumors. Therefore, if you remove the “tumor initiating cells”, then the remaining tumor cells would eventually die without any further treatment. This is called “tumor regression”. The second event is that a protein, called “midkine” is released that promotes the proliferation and survival of this small subset of cancer initiating cells. If the cancer initiating cells lack the “midkine” protein, they will not survive, and tumors will regress. Our experiments will use methods to eliminate: the cancer initiating cells, midkine expression, or both (the initiating cells and midkine). We will then track the tumor development in our model system. Successful completion of these studies will identify new targets for treating patients with deadly liver metastases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Bruce R. Ksander, Ph.D.