# Molecular Pathophysiology of Thyroid Cell Growth

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $426,550

## Abstract

Abstract:
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.

## Key facts

- **NIH application ID:** 9828528
- **Project number:** 5R01CA050706-28
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** JAMES A FAGIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,550
- **Award type:** 5
- **Project period:** 1989-08-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828528

## Citation

> US National Institutes of Health, RePORTER application 9828528, Molecular Pathophysiology of Thyroid Cell Growth (5R01CA050706-28). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828528. Licensed CC0.

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