The Role of Neuropeptide Y and Its Y5 Receptor in Dissemination of Refractory Neuroblastoma
Neuroblastoma (NB) is a pediatric cancer that presents with heterogeneous clinical phenotypes. While patients classified in the low- and intermediate-risk categories have a favorable prognosis, patients with high-risk, metastatic disease have a survival rate of only 40-50%. Despite an initial response to treatment, 50-60% of high-risk patients experience relapse and no known curative treatments are available. It has been hypothesized that a drug-resistant population of metastatic NB cells that survives chemotherapy triggers disease recurrence and thus gives rise to poor clinical outcomes. As NB is derived from precursors of sympathetic neurons, it expresses neuronal markers, including neuropeptide Y (NPY) and its Y5 receptor (Y5R). Inducible expression of Y5R has been shown to promote cell survival under stressful conditions, such as hypoxia, low oxygen level often developing in fast-growing tumors and exposure to chemotherapy. Furthermore, our lab has established that Y5R was present in all post-chemotherapy NB cell lines and that Y5R was highly expressed in a specific fraction of tumor cells that migrated towards blood vessels and invaded them.
Thus, we hypothesize that Y5R is a marker of metastatic and chemoresistant NB and that the NPY/Y5R pathway may be particularly important in dissemination of the refractory disease. The overall goal of this project is to identify potential mechanisms by which Y5R mediates these processes. Our preliminary results indicate that Y5R and active RhoA co-localize in migrating cells, suggesting that RhoA, an important regulator of cell movement, may mediate pro-metastatic effects of the NPY/Y5R pathway. Furthermore, our work suggests a role for hypoxia in mediating the transition to a malignant, chemoresistant cellular phenotype. In NB cell lines derived from tumors at diagnosis, which have low Y5R expression, Y5R was markedly up-regulated under hypoxic conditions to levels observed in post-chemotherapy NB cells. Thus, in the current project, we will determine: 1) how tumor hypoxia regulates the NPY system in NB; 2) the role of the NPY/Y5R/RhoA pathway in NB cell migration; and 3) mechanisms of Y5R-induced cell motility and strategies preventing it. Analyses will be performed on NB cell lines derived from pre- and post-chemotherapy tumors. This project will augment our understanding of Y5R's contribution to NB metastasis and chemoresistance, further validating Y5R as a marker of aggressive disease and a potentially valuable target for novel therapies for NB patients.
Mentored by Dr. Joanna Kitlinska
Georgetown University, Washington D.C.