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dc.contributor.advisorTurner, Christopher
dc.contributor.authorGoreczny, Gregory
dc.date.accessioned2021-06-10T19:41:50Z
dc.date.available2021-06-10T19:41:50Z
dc.date.issued2017
dc.identifier.urihttp://hdl.handle.net/20.500.12648/1762
dc.description.abstractHic-5 (TGFβ1i1) is a focal adhesion scaffold protein that has previously been implicated in many cancer-related processes. However, the contribution of Hic-5 during tumor progression has never been evaluated, in vivo. In Chapter 2 of this thesis, I crossed our Hic-5 knockout mouse with the MMTV-PyMT breast tumor mouse model to assess the role of Hic-5 in breast tumorigenesis. Tumors from the Hic-5 -/-;PyMT mouse exhibited an increased latency and reduced tumor growth. Immunohistochemical analysis of the Hic-5 -/-;PyMT tumors revealed that the tumor cells were less proliferative. However isolated tumor cells exhibit no difference in growth rate. Surprisingly, Hic-5 expression was restricted to the tumor stroma. Further analysis showed that Hic-5 regulates Cancer Associated Fibroblast (CAF) contractility and differentiation which resulted in a reduced ability to deposit and reorganize the extracellular matrix (ECM) in two-and three-dimensions. Furthermore, Hic-5 dependent ECM remodeling supported the ability of tumor cells to metastasize and colonize the lungs.The molecular mechanisms by which CAFs mediate ECM remodeling remains incompletely understood. In Chapter 3 of this thesis, I show that Hic-5 is required to generate fibrillar adhesions, which are specialized structures that are critical for the assembly of fibronectin fibers. Hic-5 was found to promote fibrillar adhesion formation through a newly characterized interaction with tensin1, a scaffold protein that binds to β1 integrin and actin. Furthermore, this interaction was mediated by Src-dependent phosphorylation of Hic-5 in two and three-dimensional matrix environments to prevent β1 integrin internalization and subsequent degradation in the lysosome. This work highlights the importance of the focal adhesion protein, Hic-5 during breast tumorigenesis and provides insight into the molecular machinery driving CAF-mediated ECM remodeling.en_US
dc.language.isoen_USen_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectCharacterizationen_US
dc.subjectHic-5en_US
dc.subjectCanceren_US
dc.subjectFibroblastsen_US
dc.subjectRoleen_US
dc.subjectExtracellular Matrix Depositionen_US
dc.subjectRemodelingen_US
dc.titleCharacterization of Hic-5 in Cancer Associated Fibroblasts: A Role in Extracellular Matrix Deposition and Remodelingen_US
dc.typeDissertationen_US
dc.description.versionNAen_US
refterms.dateFOA2021-06-10T19:41:51Z
dc.description.institutionUpstate Medical Universityen_US
dc.description.departmentCell and Developmental Biologyen_US
dc.description.degreelevelPhDen_US
dc.identifier.oclc1035375215


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