Extracellular vesicle cargo as biomarkers and molecular drivers of germ cell cancers
Germ cell tumors are among cancers that can afflict pediatric patients, and although many patients with these cancers can be cured, the therapies are associated with significant toxicity and are not effective for some patients. Despite these deficiencies, there have been no new FDA approved therapies for germ cell tumors in over 25 years. We aim to develop new treatments based on recent discoveries that germ cell tumors send out small cellular packages, called extracellular vesicles (EVs). These EVs contain a range of different molecules that can be taken up by other cells. Importantly, in many other cancers EVs have been shown to strongly promote tumor growth. We have recently shown that EVs from germ cell tumors contain at least two types of molecules that are likely to contribute to tumor growth. One group of molecules we detected in germ cell tumor-derived EVs are small RNA molecules called miRNAs. These miRNAs can be detected in the serum of patients and are the basis for new clinical tests to identify malignant germ cell tumors in patients. In addition, we found that germ cell tumor-derived EVs contain several metabolites that seem likely to further cancer-like growth of cells. These miRNAs and metabolites represent potential therapeutic targets to improve germ cell tumor treatment. However, almost nothing is known about the mechanisms by which these miRNAs and metabolites promote disease progression; here, we seek to address those key knowledge gaps.
Project Goals
In order to develop new treatment approaches, we must understand how the miRNAs and metabolites contained in the EVs promote cancer growth. Our first goal is to test how deleting miRNAs affects the ability of germ cell tumor cells to be tumorigenic as well as to send signals to surrounding cells that help the cancer spread. Next, we will thoroughly catalog the metabolites in the EVs released by germ cell tumor cells. We will then test the hypothesis that these contents of the EVs that germ cell tumors shed contribute to germ cell tumorigenesis and therefore represent potential therapeutic targets to improve germ cell tumor treatment. This hypothesis will be tested with a genetically engineered mouse germ cell tumor model that we created. This will allow us to study these molecular mechanisms and to test how disrupting the production of functional EVs impacts these cancers. Our studies will lay the foundation for developing new treatment approaches based on targeting miRNAs and the production of the cancerpromoting metabolites, which we believe will lead to clinical advances that significantly improve outcomes for pediatric germ cell tumor patients. Furthermore, the metabolites released from cancer cells may serve as useful markers within blood samples to detect the presence of germ cell tumor cells at very early stages and without the need for imaging studies or tissue biopsies.
