Thyroid cancer is the most common endocrine malignancy, and is one of the few cancers in which incidence is increasing. Patients diagnosed with well differentiated thyroid cancers have an excellent prognosis; however patients with poorly differentiated thyroid cancer (PDTC) have a very poor prognosis because these tumors do not respond to currently approved cancer therapeutics. The cellular and non-cellular components of the tumor microenvironment (TME) dictate tumor progression and response to therapy in many different types of human cancers; however, whether or not the TME contributes to thyroid cancer progression and the poor outcome associated with PDTC patients is unexplored. The goal of this dissertation project is to define mechanisms by which the TME of thyroid cancer contributes to disease progression and resistance to therapy. Mitogen activated protein kinase (MAPK) signaling is a driving force in thyroid carcinogenesis, as evidenced by a high prevalence of activating mutation in MAPK pathway effectors in thyroid adenomas and carcinomas. In patients, BRAF mutations are highly prevalent in papillary thyroid cancer (PTC) and do not occur in follicular thyroid cancer (FTC), while RAS mutations are associated with FTC. We utilized mouse models of Braf-driven PTC (BrafV600E/ Pten -/-/TPO-Cre) and Ras-driven FTC (HrasG12V /Pten-/-/TPO-Cre) that both progress to PDTC and defined the distinct TMEs of these tumors. We found that activation of Braf leads to the formation of a fibrotic tumor stroma enriched with fibroblasts and type 1 collagen (Col 1), which enhances tumor cell motility, representing a mechanism by which the TME contributes to disease progression. Activation of Ras leads to the formation of an immune-rich tumor stroma comprised of myeloid derived suppressor cells (MDSCs), M2-like tumor associated macrophages (TAMs), and Foxp3+ T regulatory cells (Tregs), cell types that have been shown to directly augment metastasis and immune escape in human cancers. Further, stable tumor cell lines isolated from Hras G12V/Pten-/-/TPO-Cre tumors display increased secretion of cytokines that play a direct role in promoting immune suppression and angiogenesis in human cancers, including TGFβ1 and MCSF. The work presented here demonstrates that activation of Ras versus Braf drives the formation of distinct TMEs that contribute to thyroid cancer progression, highlighting the unique biological roles of these closely related MAPK pathway effectors and their role in dictating tumor phenotype (FTC versus PTC, respectively) in thyroid cancer. Further, this work is the first to comprehensively characterize the TME of thyroid cancer, which provides valuable insight into understanding how interactions between tumor cells and their microenvironment impacts disease progression, illuminating novel therapeutic targets for thyroid cancer. We hope that gaining a better understanding of host stroma contributions to thyroid cancer progression will lead to the development and/or utilization of already clinically approved treatment strategies that target the TME, such as immunotherapies, for rare and aggressive forms of this disease for which current treatment options are limited.
|Advisor:||Franco, Aime T.|
|Commitee:||Gaddy, Dana, Simmen, Frank, Simmen, Rosalia, Suva, Larry|
|School:||University of Arkansas for Medical Sciences|
|Department:||Physiology and Biophysics|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 77/11(E), Dissertation Abstracts International|
|Subjects:||Biology, Cellular biology|
|Keywords:||BRAF, Cancer, MAPK, RAS, Thyroid, Tumor microenvironment|
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