Papillary thyroid cancers (PTC) are associated with a high prevalence of non-overlapping mutations of RET, TRK, RAS, and BRAF. As these signaling proteins form part of the classical MAPK pathway, this has been interpreted as evidence for a critical role of MAPK activation in initiation and maintenance of thyroid cancer. However thyroid cancers are also associated with mutations of genes encoding effectors signaling along the phosphatidylinositol 3-kinase (PI3K) pathway, yet whether constitutive activation of PI3K-AKT cooperates or not in certain thyroid tumors with MAPK to drive the tumorigenic process is unknown. RAS oncoproteins signal through both pathways, whereas oncogenic BRAF signals preferentially through MAPK, providing a useful paradigm in which to explore these interactions in mouse cancer models. The intensity of the oncogenic signal is an important variable, and we intend to look at these interactions through genetic manipulations that approximate pathophysiological conditions. For this we have generated mice with a conditionally gene-targeted activating mutation of H-ras, and obtained an analogous model for B-raf. 1) We will explore whether these oncoproteins initiate cell transformation through induction of a DNA damage response, followed by senescence. 2) We will expand on our observation that a thyroid-specific knock-in of H-ras markedly increases mutation frequency in mice, by using mouse reporter strains to test for different mutation types. 3) We will then examine whether H-ras or B-raf activation cooperate with loss of the tumor suppressor Pten to promote thyroid tumorigenesis in different genetic backgrounds, and explore the mechanisms involved. 4) Finally, we will test the hypothesis that genetic determinants of MAPK and PI3K activation in a large panel of suitably genotyped human thyroid cancer cell lines predicts responsiveness to pathway inhibitors. Public Health Relevance Statement: In this proposal, we intend to use mouse models to reconstruct the very first stages of thyroid cancer development. The very first genetic changes that get the tumor started are particularly important, because cancers remain dependent on their abnormal activity even though they continue to accumulate damage of other genes over time. This will help us decide what key genetic abnormalities to focus on as we develop specific treatments for patients with the most advanced forms of the disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Landa, Iñigo; Ibrahimpasic, Tihana; Boucai, Laura et al. (2016) Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 126:1052-66
Nagarajah, James; Le, Mina; Knauf, Jeffrey A et al. (2016) Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine. J Clin Invest 126:4119-4124
Garcia-Rendueles, Maria E R; Ricarte-Filho, Julio C; Untch, Brian R et al. (2015) NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition. Cancer Discov 5:1178-93
Dunn, Lara; Fagin, James A (2015) Therapy: Lenvatinib and radioiodine-refractory thyroid cancers. Nat Rev Endocrinol 11:325-7
Malaguarnera, Roberta; Chen, Kuen-Yuan; Kim, Tae-Yong et al. (2014) Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines. J Clin Endocrinol Metab 99:E1976-87
Chen, X; Makarewicz, J M; Knauf, J A et al. (2014) Transformation by Hras(G12V) is consistently associated with mutant allele copy gains and is reversed by farnesyl transferase inhibition. Oncogene 33:5442-9
Landa, Iñigo; Ganly, Ian; Chan, Timothy A et al. (2013) Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab 98:E1562-6
Gild, Matti L; Landa, Iñigo; Ryder, Mabel et al. (2013) Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells. Endocr Relat Cancer 20:659-67
Ryder, Mabel; Gild, Matti; Hohl, Tobias M et al. (2013) Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS One 8:e54302
Ricarte-Filho, Julio C; Li, Sheng; Garcia-Rendueles, Maria E R et al. (2013) Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. J Clin Invest 123:4935-44

Showing the most recent 10 out of 50 publications