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Updated: Sep 5, 2025
Spontaneous Murine Model of Anaplastic Thyroid Cancer
Published on: February 3, 2023
Blocking CDK7-Mediated NOTCH1-cMYC Signaling Attenuates Cancer Stem Cell Activity in Anaplastic Thyroid Cancer
Woo Kyung Lee Doolittle1, Li Zhao1, Sheue-Yann Cheng1
1Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Abstract:
Anaplastic thyroid cancer (ATC) is an aggressive solid cancer in humans with few treatment options. Recent studies suggest that aberrant gene transcription could contribute to aggressive ATC progression. To test this hypothesis, we assessed if blocking cyclin-dependent protein 7 (CDK7) activity could impede ATC progression through attenuation of cancer stem cell (CSC) activity. We treated cell lines isolated from human ATC (THJ-11T and -16T) and xenograft mice induced by these cells with the CDK7 inhibitor THZ1. Through integrative transcriptome analyses we found that the NOTCH1-cMYC signaling axis was a potential target of CDK7 inhibition in ATC. To determine the regulatory action of NOTCH1-cMYC signaling in CSC maintenance, we evaluated the effect of a selective NOTCH1 inhibitor, crenigacestat, on CSC capacities in ATC. THZ1 markedly inhibited proliferation of ATC cells and xenograft tumor growth by blocking cell cycle progression and inducing apoptosis. NOTCH1 was sensitive to suppressive transcription mediated by CDK7 inhibition and was highly enriched in tumorspheres from ATC cells. Treatment of ATC cells with either crenigacestat or THZ1 blocked formation of tumorspheres, decreased aldehyde dehydrogenase activity, and suppressed in vivo initiation and growth of tumors induced by ATC cells, indicating that NOTCH1 was a critical regulator of CSC activity in ATC. Furthermore, we demonstrated that cMYC was a downstream target of NOTCH1 signaling that collaboratively maintained CSC activity in ATC. Of note, genomic analysis showed that low CDK7 expression contributed to longer disease-free survival of thyroid cancer patients. NOTCH1 is a newly identified CSC regulator. Targeting NOTCH1-cMYC signaling is a promising therapeutic strategy for ATC.
Insights
Blocking cyclin-dependent protein 7 (CDK7) inhibits anaplastic thyroid cancer (ATC) by targeting the NOTCH1-cMYC pathway. This approach reduces cancer stem cell activity and tumor growth, offering a new therapeutic strategy for aggressive ATC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited therapeutic options.
- Aberrant gene transcription is implicated in ATC progression.
- Cancer stem cells (CSCs) play a crucial role in ATC aggressiveness and treatment resistance.
Purpose of the Study:
- To investigate if inhibiting cyclin-dependent protein 7 (CDK7) can impede ATC progression by reducing CSC activity.
- To identify the molecular mechanisms underlying CDK7 inhibition's effects on ATC.
- To evaluate the therapeutic potential of targeting the NOTCH1-cMYC signaling axis in ATC.
Main Methods:
- Treatment of human ATC cell lines (THJ-11T, -16T) and xenograft mouse models with the CDK7 inhibitor THZ1.
- Integrative transcriptome analysis to identify molecular targets of CDK7 inhibition.
- Evaluation of a selective NOTCH1 inhibitor, crenigacestat, on CSC properties.
- Assessment of cell proliferation, apoptosis, cell cycle progression, tumorsphere formation, aldehyde dehydrogenase activity, and in vivo tumor initiation and growth.
Main Results:
- THZ1 significantly inhibited ATC cell proliferation and xenograft tumor growth by inducing apoptosis and blocking cell cycle progression.
- CDK7 inhibition suppressed the NOTCH1-cMYC signaling axis, a key regulator of CSCs in ATC.
- Both THZ1 and crenigacestat treatments reduced CSC capacities, including tumorsphere formation and in vivo tumorigenicity.
- Low CDK7 expression correlated with improved disease-free survival in thyroid cancer patients.
Conclusions:
- NOTCH1 is a critical regulator of CSC activity in anaplastic thyroid cancer.
- Targeting the NOTCH1-cMYC signaling pathway represents a promising therapeutic strategy for ATC.
- CDK7 inhibition effectively targets CSCs and offers a potential treatment avenue for aggressive thyroid cancer.
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