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Principal Investigator: Erik S Welf
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2019
Award: $116,100
Funding agency: National Cancer Institute
DESCRIPTION (provided by applicant): A greater understanding of the mechanisms mediating melanoma metastasis is necessary for treatment of advanced disease. Because all melanoma cells must move through and survive in non-native tissue microenvironments during metastatic dissemination, the ability to migrate and survive in these microenvironments is critical
for metastatic potential. We and others have observed that melanoma cells encapsulated in 3-dimensional extracellular matrices that mimic soft tissues exhibit spontaneous and continuous non-apoptotic membrane blebbing. These observations have led us to ask if membrane blebbing is associated with the ability to survive and migrate through soft tissues. We propose to study the mechanisms that may enable melanoma migration and survival during metastatic dissemination as a function of membrane blebbing. Thus, the scientific objective of this project is to determine how blebbing is related to metastatic dissemination in melanoma. At the completion of this project, we will have determined if blebbing is enriched in stage III melanoma samples that exhibit efficient metastasis compared to stage III samples that exhibit less efficient
metastasis, and we will have determined if these differences in metastatic efficiency are mediated by the scaffolding function of the ERM family protein ezrin. We will have determined if the spatiotemporal organization of phospholipid signaling regulates ezrin phosphorylation to organize membrane blebs that facilitate cell migration in 3D matrices, and we will have determined if membrane blebbing facilitates survival signaling by regulating the spatial partitioning of ezrin between membrane and cytosolic compartments. The training objective of this proposal is to train Dr. Erik Welf in the skills required to become an independent investigato specializing in quantitative approaches to dissect the mechanisms underlying metastatic dissemination of melanoma. The proposed training activities will complement Dr. Welf's previous experience in computational modeling and analysis by providing training in the cutting edge molecular biological, imaging, and in vivo approaches necessary to study the processes of metastatic dissemination in realistic microenvironments. The proposed project leverages the expertise of faculty mentors Gaudenz Danuser and Sean Morrison, who are experts in the fields of live cell imaging and in vivo approaches, respectively. The dynamic interplay between analytical and experimental approaches is fundamental to the approach that Dr. Welf will apply as an independent researcher, and this training experience will complete the skills to facilitate this approach. Although few, if any, existing laboratories can boast expertise in both analytical and experimental approaches relevant to melanoma, the proposed mentorship team will enable Dr. Welf to develop the skills required to become successful in this endeavor.
Terms: <1,2-diacylglycerol><1-Phosphatidylinositol 3-Kinase><3-D><3-Dimensional><3D><Actins><Actomyosin><Affect><Binding><Binding Proteins><Biological><Bleb><Blister><Body Tissues><Brachydanio rerio><Bulla><Bullous Lesion><CD44><CD44 gene><CRISPR><CRISPR/Cas system><Cell Communication and Signaling><Cell Function><Cell Locomotion><Cell Migration><Cell Movement><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cell physiology><Cell surface><Cell-Extracellular Matrix><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Clustered Regularly Interspaced Short Palindromic Repeats><Collagen Fiber><Complement><Complement Proteins><Computer Analysis><Computer Models><Computer Simulation><Computer based Simulation><Computerized Models><Danio rerio><Data><Diacylglycerols><Diglycerides><ECM><Encapsulated><Equilibrium><Exhibits><Extracellular Matrix><Family><Family member><Genetic Alteration><Genetic Change><Genetic defect><Image><In Vitro><Intracellular Communication and Signaling><Investigators><L-Threonine><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><MDU3><Malignant Melanoma><Mathematical Model Simulation><Mathematical Models and Simulations><Measures><Mediating><Melanoma Cell><Membrane><Mentorship><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Tumor><Metastatic to><Mice><Mice Mammals><Molecular><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Motility><Murine><Mus><Mutation><Neoplasm Metastasis><Neural Crest Cell><PI-3 Kinase><PI-3K><PI3-Kinase><PIP2><Pathway interactions><Patients><Pgp1><Phosphatides><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 4,5-Biphosphate><Phosphatidylinositol 4,5-Diphosphate><Phosphatidylinositol-3-OH Kinase><Phosphatidylinositol-4,5-Bisphosphate><Phosphoinositide 3-Hydroxykinase><Phospholipids><Phosphorylation><Prevalence><Primordial Germ Cell><Process><Property><Protein Binding><Protein Family><Protein Phosphorylation><Proteins><PtIns 4,5-P2><PtdIns 3-Kinase><PtdInsP2><Receptor Protein><Research Personnel><Researchers><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of primordial sex cell><Subcellular Process><Surface><Testing><Threonine><Tissues><Training><Training Activity><Tumor Cell><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Vesication><Xenograft Model><Zebra Danio><Zebra Fish><Zebrafish><advanced disease><advanced illness><balance><balance function><biological signal transduction><bound protein><cancer metastasis><cancer progression><cell motility><computational analyses><computational analysis><computational modeling><computational models><computational simulation><computer analyses><computer based models><computerized modeling><computerized simulation><conformation><conformational state><diacylglycerol><diglyceride><experience><ezrin><faculty mentor><genome editing><genome mutation><genomic editing><imaging><in silico><in vivo><intervention design><live cell image><live cell imaging><live cellular image><live cellular imaging><melanoma><membrane structure><membrane-organizing extension spike protein><metastatic process><migration><moesin><mortality><neoplasm progression><neoplastic cell><neoplastic progression><non-Native><nonnative><pathway><phosphoprotein p81><polymerization><pressure><public health relevance><radixin><radixin protein><receptor><scaffold><scaffolding><skills><social role><soft tissue><spatiotemporal><therapy design><training module><treatment design><tumor cell metastasis><tumor progression><virtual simulation>