Metastasis is a series of process that tumor cells lose their stationary epithelial characteristics and acquire migratory mesenchymal characteristics. Metastatic cancer that spread to multiple organs is a major cause of cancer mortality and morbidity. Thus, new rationally designed therapies are urgently needed to control, cure and prevent invasive cancers. Understanding the molecular mechanisms for the acquisition of highly invasive characteristics will contribute to developing new therapies for preventing and treating cancers. Growing evidence suggests that one of the critical signaling cascades for the acquisition of highly invasive characteristics is Notch signaling. Notch signaling plays a well-characterized role in cell fate specifications, stem cell renewals, and cell differentiation. However, the role in determining invasive cell characteristics remains poorly understood. Our long-term goal is to elucidate the molecular mechanisms by which Notch signaling and its modulators determines the invasive cell characteristics, thus serving as a necessary prerequisite to developing new therapeutic protocols for treating and preventing cancers. The hypothesis of our proposed research is that an essential modulator of Notch signaling, Mind bomb (Mib), plays a critical role in establishing and maintaining epithelial cell morphology not only by promoting Notch signaling but also by directly regulating epithelial cell polarity formation. The zebrafish is an excellent vertebrate model system to visualize the behavior of individual cells. In this study we use the zebrafish sensory organ, the posterior lateral line (pLL), as a model system to demonstrate these dual roles of Mib in epithelial morphogenesis. We based our hypothesis on the following observations that 1)mib mutants show aberrant epithelial morphogenesis, 2)embryos manipulated to loss of Notch activity show morphological defects, but do not completely phenocopy mib mutants, and 3)a Mib interacting protein, Epb4.1l5, regulates epithelial polarity formation. Based on these observations, the specific aims are to 1)define the Notch-dependent and independent function of Mib in pLL morphogenesis, and 2)characterize the molecular mechanism of Notch-independent Mib function in epithelial morphogenesis. More than 500,000 Americans lost their lives to metastatic cancer in 2008. In this proposed study, we use the zebrafish to understand the molecular mechanism of epithelial morphogenesis. The successful completion of our proposed research will be applicable to understanding molecular mechanisms by which stationary epithelial cells acquire the highly invasive cell characteristic in our bodies. It will lead to new therapies that effectively prevent and treat invasive cancers.
Metastasis is a series of process that tumor cells lose their stationary epithelial characteristics and acquire migratory mesenchymal characteristics. More than 500,000 Americans lost their lives to metastatic cancer in 2008. Understanding the molecular mechanisms for the acquisition of highly invasive characteristics will contribute to developing therapeutic protocols for preventing and treating cancers.
|Matsuda, Miho; Rand, Kinneret; Palardy, Greg et al. (2016) Epb41l5 competes with Delta as a substrate for Mib1 to coordinate specification and differentiation of neurons. Development 143:3085-96|
|Matsuda, Miho; Nogare, Damian Dalle; Somers, Katherine et al. (2013) Lef1 regulates Dusp6 to influence neuromast formation and spacing in the zebrafish posterior lateral line primordium. Development 140:2387-97|
|Chitnis, Ajay B; Nogare, Damian Dalle; Matsuda, Miho (2012) Building the posterior lateral line system in zebrafish. Dev Neurobiol 72:234-55|
|Matsuda, Miho; Chitnis, Ajay B (2010) Atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the posterior lateral line primordium in zebrafish. Development 137:3477-87|