Poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC) have a high frequency of mutations of genes encoding subunits of the SWI/SNF (BAF and PBAF) chromatin remodeling complexes. Moreover, a Sleeping Beauty transposon mutagenesis screen found that disruptions of chromatin modifiers, including Swi/Snf subunits, significantly cooperate with oncogenic Hras in progression to PDTC. The SWI/SNF complex supports terminal differentiation in multiple contexts and its loss can promote stem cell-like properties. Potent inhibition of MAPK signaling markedly augments expression of thyroid differentiation genes, increases radioactive iodine (RAI) uptake and responses to RAI therapy in mice and in patients with mutations of MAPK signaling effectors. We speculate that disruptions of SWI/SNF may lock thyroid cells into a dedifferentiated state that is no longer reversible by MAPK pathway blockade. We found that homozygous loss of Arid1a, Arid2 and Smarcb1 in the context of BrafV600E results in dedifferentiation, development of PDTC and ATCs and decreased survival. Although Swi/Snf subunit loss results in a more compact and inaccessible chromatin landscape, it paradoxically also increases chromosome accessibility to sites that are enriched for DNA motifs that predict for activation of transcriptional programs mediating disease progression and trans-differentiation, and generate potential therapeutic dependencies. For instance, these tumors have a robust activation of the Hedgehog pathway and exquisite sensitivity to the Gli antagonist GANT61, but not to upstream inhibitors of the pathway. We will now pursue the following aims: 1. Investigate the impact of Arid1a, Arid2 and Smarcb1 loss on thyroid tumorigenesis in GEM models and on the chromatin and transcriptional landscape. 2. Identify novel dependencies arising from Arid1a, Arid2 and Smarcb1 loss in Braf-mutant thyroid cancers, and test the hypothesis that Swi/Snf loss augments the MAPK transcriptional output distal to the phosphorylation cascade mediated by its signaling effectors. We will also determine whether Swi/Snf loss poises cells to trans-differentiate towards non-thyroidal lineages, and explore the mechanisms involved. 3. Determine whether loss of Swi/Snf function impairs the ability of MAPK pathway inhibitors to restore thyroid differentiation in Braf-driven thyroid cancers, and if so, if this can be restored by GANT61, BET domain or EZH2 inhibitors.

Public Health Relevance

Advanced forms of thyroid cancers acquire mutations of genes that are involved in remodeling chromatin, the DNA and protein material that determines which genes are active and which are not. We discovered that these mutations block the activity of key genes that determine the differentiation state of thyroid tumor cells. We aim to find out how this takes place, and whether we can find ways to reprogram the cells to restore differentiation and improve outcomes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA050706-27A1
Application #
9662278
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Yassin, Rihab R
Project Start
1989-08-01
Project End
2023-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
27
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Bellelli, Roberto; Vitagliano, Donata; Federico, Giorgia et al. (2018) Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia. Mol Cell Endocrinol 460:24-35
Krishnamoorthy, Gnana P; Davidson, Natalie R; Leach, Steven D et al. (2018) EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov :
Untch, Brian R; Dos Anjos, Vanessa; Garcia-Rendueles, Maria E R et al. (2018) Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. Cancer Res 78:4642-4657
Azouzi, Naïma; Cailloux, Jérémy; Cazarin, Juliana M et al. (2017) NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas. Antioxid Redox Signal 26:864-877
Ibrahimpasic, Tihana; Xu, Bin; Landa, Iñigo et al. (2017) Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence. Clin Cancer Res 23:5970-5980
Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu et al. (2017) Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. Proc Natl Acad Sci U S A 114:E4951-E4960
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
Fagin, James A; Wells Jr, Samuel A (2016) Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med 375:1054-67
Dogan, Snjezana; Wang, Lu; Ptashkin, Ryan N et al. (2016) Mammary analog secretory carcinoma of the thyroid gland: A primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. Mod Pathol 29:985-95

Showing the most recent 10 out of 42 publications