ingest cdrApp 2017-08-15T22:33:47.534Z d91e81c8-5a8a-4e8a-976c-cad4e396e5ee modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:34:32.690Z Setting exclusive relation modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:34:41.805Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2017-08-15T22:34:50.762Z Adding technical metadata derived by FITS modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:35:08.562Z Setting exclusive relation addDatastream MD_FULL_TEXT fedoraAdmin 2017-08-15T22:35:18.019Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2017-08-15T22:35:35.872Z Setting exclusive relation modifyDatastreamByValue RELS-EXT cdrApp 2017-08-22T13:57:15.363Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-08T14:04:55.644Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-25T09:56:45.460Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-01-27T10:05:25.988Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-03-14T06:53:04.375Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-17T18:23:29.304Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-11T05:20:54.958Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-18T01:35:00.613Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T14:46:23.810Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T01:18:12.791Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-12T01:50:13.077Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T20:01:32.906Z Hailey Brighton Author Department of Cell Biology and Physiology School of Medicine INTRAVITAL IMAGING OF MELANOMA IN COMBINATION WITH MOLECULAR ANALYSIS REVEALS KEY CHANGES IN STROMAL ECM AND TUMOR BEHAVIOR IN PERSISTENCE AGAINST MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. Summer 2017 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text Hailey Brighton Author Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. Summer 2017 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. Summer 2017 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. Summer 2017 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017-08 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 University of North Carolina at Chapel Hill Degree granting institution Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance; intravital imaging; melanoma; trametinib eng Doctor of Philosophy Dissertation Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 University of North Carolina at Chapel Hill Degree granting institution Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Intravital imaging of melanoma in combination with molecular analysis reveals key changes in stromal ECM and tumor behavior in persistence against MEKi Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance, intravital imaging, melanoma, trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Cell Biology and Physiology James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 Hailey Brighton Creator Department of Cell Biology and Physiology School of Medicine Melanoma is a devastating disease, and while a number of targeted therapies are used to treat patients with malignant melanoma, tumors become resistant. Understanding tumor response to targeted therapies and how therapeutic strategies fail is a critical challenge in modern oncology. To investigate tumor behavior and response to a selective small molecule inhibitor of MEK1/2 (Trametinib) in vivo, we developed an intravital imaging approach to directly visualize drug response in a BRAFV600E/PTEN-null mouse model of melanoma by genetically incorporating a tdTomato fluorescent reporter allele (tdTomatoLSL). Through highly localized application of tamoxifen (4-HT) and noninvasive, serial intravital microscopy, I was able to directly visualize formation and progression of tumors at the single cell level in situ longitudinally over time. I directly imaged primary tumors in mice throughout treatment with MEKi and observed changes in tumor cell behavior during drug response for twelve weeks. I identified a clear relationship between bundled collagen and tumor cell survival in response to MEKi and collaborated with the Johnson lab to couple this model with transcriptome and kinome reprogramming analysis. Molecular analysis of tumors at early and late stages on MEKi identified a phenotypic shift toward an epithelial phenotype, characterized by c-Kit activity and the induction of a EMT_down and PI3K/AKT survival pathway signatures for melanoma persistence in vivo. Together, these approaches give a holistic view of the complex changes of tumor cells and stromal tissue in response to targeted therapy and provide insight for future treatment strategies. 2017 Cellular biology Pharmacology drug resistance; intravital imaging; melanoma; trametinib eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution James Bear Thesis advisor Norman Sharpless Thesis advisor Keith Burridge Thesis advisor William Kim Thesis advisor Andrew Dudley Thesis advisor text 2017-08 Brighton_unc_0153D_17273.pdf uuid:90e01b9e-0734-4f11-a23a-15b5b87419eb 2019-08-15T00:00:00 proquest 2017-07-24T17:39:12Z application/pdf 7543829 yes