Developmental Mechanisms Driving Cell Invasion in Pediatric Brain Cancers

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PROJECT SUMMARY – HUNTSMAN CANCER INSTITUTE, RODNEY STEWART Embryonic morphogenesis mechanisms are frequently activated in human cancers, particularly childhood brain tumors. In particular, genes that regulate neural crest (NC) epithelial-to-mesenchymal transition (EMT) and cell migration, such as the Snail family of transcription factors, are often re-activated in tumor cells to promote malignant progression by changing the available repertoire of cell adhesion, cytoskeletal, apoptotic and signaling molecules. This leads to enhanced tumor-cell dissemination, self-renewal and chemo-resistance, a devastating combination that promotes treatment failure and cancer-related mortality. The long-term goal of this research is to define the essential, conserved and rate-limiting effectors of embryonic EMT programs that drive cancer progression in order to identify new targets and therapeutics that can be used alone or in conjunction with current therapeutics to eliminate tumor cells. The overall objective of the current project, which represents the next logical step toward our long-term goal, is to 1) use the powerful genetic attributes of the zebrafish system to identify new mechanisms driving NC EMT and cell migration and 2) determine if inhibiting one or more EMT effectors in a model of pediatric brain tumors prevents tumor invasion and/or dissemination. The central hypothesis is that a subset of cell adhesion, cytoskeleton and/or signaling molecules are essential for executing NC EMT and that these molecules represent promising targets to inhibit EMT-induced brain tumor invasion. Guided by published and preliminary data, this hypothesis will be tested by pursuing three specific aims in which we will: 1) determine if the highly conserved Foxd3 transcription factor directly controls the expression of Snail genes during EMT, 2) identify essential effectors of Foxd3/Snail-dependent EMT during NC development and 3) determine if one or more NC effectors are required for brain tumor invasion in vivo. The proposal is innovative because it employs new genetic and imaging technologies to dynamically measure and manipulate the impact of developmental EMT programs during brain tumor invasion in whole animals at single-cell resolution for the first time, allowing the rapid identification of new targets and therapeutics for brain cancers. The successful completion of the proposed research will have a significant impact because it is expected to vertically advance and expand our understanding of how to manipulate developmental EMT programs in a number of disease settings, including NC-derived birth defects, fibrosis and cancer invasion, thus allowing for the strategic design of effective treatments for these diseases.