Characterization of Hic-5 in Cancer Associated Fibroblasts: A Role in Extracellular Matrix Deposition and Remodeling
dc.contributor.advisor | Turner, Christopher | |
dc.contributor.author | Goreczny, Gregory | |
dc.date.accessioned | 2021-06-10T19:41:50Z | |
dc.date.available | 2021-06-10T19:41:50Z | |
dc.date.issued | 2017 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12648/1762 | |
dc.description.abstract | Hic-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.iso | en_US | en_US |
dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Characterization | en_US |
dc.subject | Hic-5 | en_US |
dc.subject | Cancer | en_US |
dc.subject | Fibroblasts | en_US |
dc.subject | Role | en_US |
dc.subject | Extracellular Matrix Deposition | en_US |
dc.subject | Remodeling | en_US |
dc.title | Characterization of Hic-5 in Cancer Associated Fibroblasts: A Role in Extracellular Matrix Deposition and Remodeling | en_US |
dc.type | Dissertation | en_US |
dc.description.version | NA | en_US |
refterms.dateFOA | 2021-06-10T19:41:51Z | |
dc.description.institution | Upstate Medical University | en_US |
dc.description.department | Cell and Developmental Biology | en_US |
dc.description.degreelevel | PhD | en_US |
dc.identifier.oclc | 1035375215 |