The overall goal of this proposal is to understand the mechanisms regulating the malignant phenotype of neuroblastoma. Neuroblastoma (NB) is the most common pediatric solid tumor, accounting for 7-10 percent of all childhood cancer. NB progresses to an aggressive, disseminated disease, termed stage IV NB, characterized by widespread dissemination of the tumor, and colonization of privileged sites, including bone marrow. Current treatments have limited success, and mortality associated with late stage disease is high (approximately 70%). One hallmark of the most malignant form of NB (stage IV) is the complete loss of caspase 8 expression. We show here that this loss of caspase 8 is associated with resistance to a form of apoptosis termed """"""""Integrin-mediated Death,"""""""" in which apoptosis is triggered by unligated cell-surface integrins. Loss of caspase 8 is associated with other alterations in integrin function, including decreased adhesion of malignant NB to ECM and increased migration/invasion. Importantly, as we show in the Preliminary Results, stable reconstitution of physiological levels of caspase 8 expression reverses each of these properties of stage IV NB in vitro. Moreover, initial studies suggest that caspase 8 re-expression blocks the metastasis of stage IV NB in vivo. We therefore propose to examine the molecular mechanisms by which caspase 8 may regulate these malignant characteristics of advanced NB. In the initial Aim, we will perform molecular mapping studies to determine how unligated integrins can recruit and activate caspase 8, promoting apoptosis among NB tumor cells in vitro. Studies outlined in Aim 2 will focus on the mechanisms by which caspase 8 increase ECM adhesion and influence the migration of NB cells. Finally, in the third Aim we will examine the impact of these events on NB progression and dissemination in vivo. An understanding of these molecular mechanisms will be crucial for the design of future therapies that target the malignant properties of NB.
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