Oral Presentation 14th International Biennial Conference on Metastasis Research 2012

Fascin is required for neural crest migration and brain tumor invasion in zebrafish (#11)

Elena Boer 1 , Katarzyna Modzelewska 1 , Cicely A Jette 1 , Rodney A Stewart 1
  1. Dept. Oncological Sciences, Huntsman Cancer Institute/University of Utah, Salt Lake City, UT, USA

Metastasis is the leading cause of death in cancer patients.  Current models support a multistep process for metastasis progression, including escape from the primary tumor, migration and survival in the circulatory system, and colonization of distant organs.   The genetic mechanisms that govern each of these steps remain incompletely understood due to a lack of appropriate genetic models of metastasis.   We use neural crest development to model metastatic dissemination because both metastatic cancer cells and neural crest cells undergo EMT, migrate collectively, and colonize distant organs.  Specifically, our research focuses on the genetic mechanisms that regulate collective cell migration, which requires the coordination of cell-cell and cell-ECM interactions through cell surface receptors and actin-rich protrusions such as filopodia.   A critical regulator of filopodia formation is the actin bundling protein Fascin, which is upregulated in many human cancers and associated with clinically aggressive tumors, metastasis, and poor survival. We combined imaging and genetic approaches in zebrafish to study the role of Fascin in collective neural crest cell migration and cancer metastasis in vivo.   We found that fascin-deficiency results in abnormal filopodia formation in neural crest cells, which causes loss of cell-cell adherence within the cranial streams, decreased cell velocity and invasion of cells into neighboring tissues.  Consistent with these defects, fascin-deficient embryos display abnormal development of cranial neural crest derivatives.  We are also using a novel zebrafish brain tumor model developed in our lab to study the requirement for Fascin in tumor invasion and metastasis.  These tumors express high levels of Fascin at the invasive front and we are using genetic and pharmacological approaches to determine if Fascin is necessary and sufficient for brain tumor cell invasion and/or metastasis.