Role of BRAF mutation in thyroid cancer invasion: Thyroid cancer is a common malignancy associated with substantial morbidity. Well-differentiated thyroid cancer is the most common endocrine malignancy and ranks as the seventh most common cancer diagnosed in women. Increasing incidence of thyroid cancer over the past few decades is reflected by the projected 37,000 new cases in 2009. While the majority of patients with well-differentiated thyroid cancer presents with limited disease and become disease-free after initial treatment, 20% of patients with thyroid cancer have local or regional recurrent disease, and 5% develop distant metastases. Prior studies have identified the BRAF gene as the most commonly mutated in papillary thyroid cancer, activation of this pathway leads to ERK translocation and downstream transcriptional dysregulation. This mutation is implicated in the initiation and progression of aggressive subtypes such as tall cell, and in those with extra-thyroidal extension, lymph nodal and distant metastases. Moreover, it is associated with both loss of radioiodine avidity and cancer recurrence. The mechanisms by which this mutation induces invasion and distant spread are not fully understood. We have recently carried out a detailed Gene Set Enrichment Analysis to analyze the genomic signature of papillary thyroid cancer patients with or without this BRAF mutation. We have found that BRAFV600E mutation results in the alteration of several cell adhesion molecules including Thrombospondin-1, integrins and other stromally active proteases, such as matrix metalloproteases. Here we posit that BRAF mutation and changes in these adhesion molecules plays a crucial role in the invasion and metastasis of the most aggressive and non-curable forms of papillary thyroid cancer. In addition, we postulate that selective BRAF inhibitors that are currently being validated in several forms of cancer could be utilized in the treatment of the thyroid cancers harbouring BRAF mutation. Our goal is to characterize the role of BRAF V600E mutation, as well as BRAF induced expression of TSP-1, matrix metalloproteases and other ECM molecules in thyroid cancer cell lines, as well as a novel preclinical mouse model of thyroid cancer. We also plan to test the efficacy of BRAFV600E specific inhibitors and to determine whether TSP-1, and MMPs could be utilized as a diagnostic biomarker for detection of the aggressive forms of thyroid cancer as well as therapeutic biomarkers to evaluate the response to BRAF inhibitors.

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Role of BRAF mutation in thyroid cancer invasion Analyzing how BRAFV600E mutation alters critical molecules involved in thyroid tumor cell migration and leads to invasion and metastasis in the most aggressive and non-curable forms of papillary thyroid cancer.

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National Cancer Institute (NCI)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Snyderwine, Elizabeth G
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Massachusetts General Hospital
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Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215
Gopal, Raj K; Kübler, Kirsten; Calvo, Sarah E et al. (2018) Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hürthle Cell Carcinoma. Cancer Cell 34:242-255.e5
Lubitz, Carrie C; Zhan, Tiannan; Gunda, Viswanath et al. (2018) Circulating BRAFV600E Levels Correlate with Treatment in Patients with Thyroid Carcinoma. Thyroid 28:328-339
Gunda, Viswanath; Sarosiek, Kristopher A; Brauner, Eran et al. (2017) Inhibition of MAPKinase pathway sensitizes thyroid cancer cells to ABT-737 induced apoptosis. Cancer Lett 395:1-10
Varmeh, Shohreh; Vanden Borre, Pierre; Gunda, Viswanath et al. (2016) Genome-wide analysis of differentially expressed miRNA in PLX4720-resistant and parental human thyroid cancer cell lines. Surgery 159:152-62
Brauner, Eran; Gunda, Viswanath; Vanden Borre, Pierre et al. (2016) Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer. Oncotarget 7:17194-211
Liu, Yanlan; Gunda, Viswanath; Zhu, Xi et al. (2016) Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer. Proc Natl Acad Sci U S A 113:7750-5
Lubitz, Carrie C; Parangi, Sareh; Holm, Tammy M et al. (2016) Detection of Circulating BRAF(V600E) in Patients with Papillary Thyroid Carcinoma. J Mol Diagn 18:100-8
Vanden Borre, Pierre; Gunda, Viswanath; McFadden, David G et al. (2014) Combined BRAF(V600E)- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer. Oncotarget 5:3996-4010
Gunda, V; Bucur, O; Varnau, J et al. (2014) Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways. Cell Death Dis 5:e1104

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