ingest cdrApp 2018-08-23T18:42:53.029Z d39a25df-af15-48e9-aec2-c9af81a997a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T18:43:43.668Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-08-23T18:43:54.952Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-08-23T18:44:17.683Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T18:44:29.108Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T02:10:04.074Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-20T20:57:52.241Z Ashley Fuller Author Department of Pathology and Laboratory Medicine School of Medicine Triple-negative breast cancer microenvironments: Molecular and histologic portraits Triple-negative breast cancer (TNBC), comprised predominantly of the basal-like (BBC) and claudin-low (CLBC) intrinsic subtypes, is a proliferative, invasive disease that accounts for 15-20% of breast cancer cases. Unlike with other breast cancer subtypes, TNBC treatment modalities are generally limited to surgery, radiation, and cytotoxic chemotherapy. Therefore, identification of molecular contributors to TNBC initiation and progression, including signals with relevance to the tumor microenvironment, is important for development of biologically targeted therapies. It is well accepted that the tumor microenvironment, the non-cancerous cells and tissues in proximity to the frank cancer cells, plays a critical role in breast cancer initiation and progression. However, little is known about the evolution of stromal-epithelial communication during breast tumorigenesis, or how specific signaling mediators alter subtype-specific tumor behavior. To this end, this work leveraged a suite of model systems to better understand how specific components of TNBC microenvironments influence tumor phenotypes and stromal-epithelial interactions. Following a literature review in Chapter 1, Chapter 2 describes research that used three-dimensional culture models of a pre-invasive BBC cell line panel, together with novel imaging technology, to evaluate cancer cell-fibroblast interactions during early stages of tumor initiation. Relative to wild-type cells, pre-invasive BBC cells lacking the TP53 tumor suppressor gene exhibited accelerated and unique responses to fibroblast co-culture. In Chapter 3, the role of the immune microenvironment in TNBC progression was evaluated using a novel animal model. Myeloid-specific Glut1 knockout mice were used to demonstrate that alterations in myeloid cell metabolism reduced the inflammatory potential of mammary tissue macrophages (MTMs) and impeded CLBC progression. Chapter 4 leveraged observational studies of human tissue to develop a digital algorithm to identify histologically stained endothelial cells in cancer-adjacent breast. This algorithm will be used in future studies to quantitatively characterize the vascular microenvironment both across breast cancer subtypes, and for TNBCs in particular. Finally, Chapter 5 integrates insights from all three investigations to identify future directions for studies of TNBC microenvironments. This work reveals previously uncharacterized relationships between TNBCs and their associated stromal cells, some of which may represent plausible therapeutic targets for this tumor subtype. Summer 2018 2018 Oncology Basal-like breast cancer, Claudin-low breast cancer, Co-culture, Normal breast, Slc2a1, Tumor microenvironment eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pathology Melissa Troester Thesis advisor William Coleman Thesis advisor Stephen Hursting Thesis advisor Liza Makowski Thesis advisor Cyrus Vaziri Thesis advisor text Ashley Fuller Creator Department of Pathology and Laboratory Medicine School of Medicine Triple-negative breast cancer microenvironments: Molecular and histologic portraits Triple-negative breast cancer (TNBC), comprised predominantly of the basal-like (BBC) and claudin-low (CLBC) intrinsic subtypes, is a proliferative, invasive disease that accounts for 15-20% of breast cancer cases. Unlike with other breast cancer subtypes, TNBC treatment modalities are generally limited to surgery, radiation, and cytotoxic chemotherapy. Therefore, identification of molecular contributors to TNBC initiation and progression, including signals with relevance to the tumor microenvironment, is important for development of biologically targeted therapies. It is well accepted that the tumor microenvironment, the non-cancerous cells and tissues in proximity to the frank cancer cells, plays a critical role in breast cancer initiation and progression. However, little is known about the evolution of stromal-epithelial communication during breast tumorigenesis, or how specific signaling mediators alter subtype-specific tumor behavior. To this end, this work leveraged a suite of model systems to better understand how specific components of TNBC microenvironments influence tumor phenotypes and stromal-epithelial interactions. Following a literature review in Chapter 1, Chapter 2 describes research that used three-dimensional culture models of a pre-invasive BBC cell line panel, together with novel imaging technology, to evaluate cancer cell-fibroblast interactions during early stages of tumor initiation. Relative to wild-type cells, pre-invasive BBC cells lacking the TP53 tumor suppressor gene exhibited accelerated and unique responses to fibroblast co-culture. In Chapter 3, the role of the immune microenvironment in TNBC progression was evaluated using a novel animal model. Myeloid-specific Glut1 knockout mice were used to demonstrate that alterations in myeloid cell metabolism reduced the inflammatory potential of mammary tissue macrophages (MTMs) and impeded CLBC progression. Chapter 4 leveraged observational studies of human tissue to develop a digital algorithm to identify histologically stained endothelial cells in cancer-adjacent breast. This algorithm will be used in future studies to quantitatively characterize the vascular microenvironment both across breast cancer subtypes, and for TNBCs in particular. Finally, Chapter 5 integrates insights from all three investigations to identify future directions for studies of TNBC microenvironments. This work reveals previously uncharacterized relationships between TNBCs and their associated stromal cells, some of which may represent plausible therapeutic targets for this tumor subtype. Oncology Basal-like breast cancer; Claudin-low breast cancer; Co-culture; Normal breast; Slc2a1; Tumor microenvironment Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Pathology Melissa Troester Thesis advisor William Coleman Thesis advisor Stephen Hursting Thesis advisor Liza Makowski Thesis advisor Cyrus Vaziri Thesis advisor 2018 2018-08 eng text Ashley Fuller Creator Department of Pathology and Laboratory Medicine School of Medicine Triple-negative breast cancer (TNBC), comprised predominantly of the basal-like (BBC) and claudin-low (CLBC) intrinsic subtypes, is a proliferative, invasive disease that accounts for 15-20% of breast cancer cases. Unlike with other breast cancer subtypes, TNBC treatment modalities are generally limited to surgery, radiation, and cytotoxic chemotherapy. Therefore, identification of molecular contributors to TNBC initiation and progression, including signals with relevance to the tumor microenvironment, is important for development of biologically targeted therapies. It is well accepted that the tumor microenvironment, the non-cancerous cells and tissues in proximity to the frank cancer cells, plays a critical role in breast cancer initiation and progression. However, little is known about the evolution of stromal-epithelial communication during breast tumorigenesis, or how specific signaling mediators alter subtype-specific tumor behavior. To this end, this work leveraged a suite of model systems to better understand how specific components of TNBC microenvironments influence tumor phenotypes and stromal-epithelial interactions. Following a literature review in Chapter 1, Chapter 2 describes research that used three-dimensional culture models of a pre-invasive BBC cell line panel, together with novel imaging technology, to evaluate cancer cell-fibroblast interactions during early stages of tumor initiation. Relative to wild-type cells, pre-invasive BBC cells lacking the TP53 tumor suppressor gene exhibited accelerated and unique responses to fibroblast co-culture. In Chapter 3, the role of the immune microenvironment in TNBC progression was evaluated using a novel animal model. Myeloid-specific Glut1 knockout mice were used to demonstrate that alterations in myeloid cell metabolism reduced the inflammatory potential of mammary tissue macrophages (MTMs) and impeded CLBC progression. Chapter 4 leveraged observational studies of human tissue to develop a digital algorithm to identify histologically stained endothelial cells in cancer-adjacent breast. This algorithm will be used in future studies to quantitatively characterize the vascular microenvironment both across breast cancer subtypes, and for TNBCs in particular. Finally, Chapter 5 integrates insights from all three investigations to identify future directions for studies of TNBC microenvironments. This work reveals previously uncharacterized relationships between TNBCs and their associated stromal cells, some of which may represent plausible therapeutic targets for this tumor subtype. Oncology Basal-like breast cancer; Claudin-low breast cancer; Co-culture; Normal breast; Slc2a1; Tumor microenvironment Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Melissa Troester Thesis advisor William Coleman Thesis advisor Stephen Hursting Thesis advisor Liza Makowski Thesis advisor Cyrus Vaziri Thesis advisor 2018 2018-08 eng text Fuller_unc_0153D_18001.pdf uuid:71d948ef-c198-4502-9d7b-92c1c5cdc010 2020-08-23T00:00:00 2018-07-16T22:00:48Z proquest application/pdf 3667476