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Updated: Jul 30, 2025
Establishment and Characterization of Patient-Derived Xenograft Models of Anaplastic Thyroid Carcinoma and Head and Neck Squamous Cell Carcinoma
Published on: June 2, 2023
The Tyrosine Kinase Inhibitor Lenvatinib Inhibits Anaplastic Thyroid Carcinoma Growth by Targeting Pericytes in the
Asumi Iesato1,2, Stephanie Li1,2, Peter M Sadow3
1Human Thyroid Cancers Preclinical and Translational Research Program, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Abstract:
Anaplastic thyroid carcinoma (ATC) is a rapidly fatal cancer with a median survival of a few months. Enhanced therapeutic options for durable management of ATC will rely on an understanding of genetics and the role of the tumor microenvironment. The prognosis for patients with ATC has not improved despite more detailed scrutiny of underlying tumor genetics. Pericytes in the microenvironment play a key evasive role for thyroid carcinoma (TC) cells. Lenvatinib improves outcomes in patients with radioiodine-refractory well-differentiated TC. In addition to the unclear role of pericytes in ATC, the effect and mechanism of lenvatinib efficacy on ATC have not been sufficiently elucidated. We assessed pericyte enrichment in ATC. We determined the effect of lenvatinib on ATC cell growth cocultured with pericytes and in a xenograft mouse model from human BRAF-ATC-derived cells coimplanted with pericytes. ATC samples were significantly enriched in pericytes compared with normal thyroid samples. BRAF-ATC-derived cells were resistant to lenvatinib treatment shown by a lack of suppression of MAPK and Akt pathways. Moreover, lenvatinib increased CD47 protein (thrombospondin-1 [TSP-1] receptor) levels over time vs. vehicle. TSP-1 levels were downregulated upon lenvatinib at late vs. early time points. Critically, ATC cells, when cocultured with pericytes, showed increased sensitivity to this therapy and ultimately decreased number of cells. The coimplantation in vivo of ATC cells with pericytes increased ATC growth and did not downregulate TSP-1 in the microenvironment in vivo. Pericytes are enriched in ATC samples. Lenvatinib showed inhibitory effects on BRAF-ATC cells in the presence of pericytes. The presence of pericytes could be crucial for effective lenvatinib treatment in patients with ATC. Degree of pericyte abundance may be an attractive prognostic marker in assessing pharmacotherapeutic options. Effective durable management of ATC will rely on an understanding not only of genetics but also on the role of the tumor microenvironment.
Insights
Pericytes are abundant in anaplastic thyroid carcinoma (ATC). Lenvatinib drug efficacy against ATC cells is enhanced by pericytes, suggesting their crucial role in treatment.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment Research
Background:
- Anaplastic thyroid carcinoma (ATC) is an aggressive cancer with poor prognosis and limited treatment options.
- The tumor microenvironment, particularly pericytes, plays a significant role in cancer progression and treatment resistance.
- Lenvatinib shows efficacy in differentiated thyroid cancer, but its role and mechanism in ATC remain unclear.
Purpose of the Study:
- To investigate the enrichment of pericytes in anaplastic thyroid carcinoma (ATC) samples.
- To determine the effect of lenvatinib on ATC cell growth in the presence of pericytes, both in vitro and in vivo.
- To elucidate the potential role of pericytes in modulating lenvatinib efficacy in ATC.
Main Methods:
- Assessment of pericyte enrichment in human ATC samples compared to normal thyroid tissue.
- In vitro coculture of BRAF-mutant ATC cells with pericytes to evaluate lenvatinib response.
- In vivo xenograft mouse model using co-implanted ATC cells and pericytes to assess lenvatinib efficacy and microenvironmental changes.
Main Results:
- ATC samples exhibited significant pericyte enrichment compared to normal thyroid tissue.
- BRAF-ATC cells showed resistance to lenvatinib alone, with no suppression of MAPK and Akt pathways.
- Pericyte co-culture increased ATC cell sensitivity to lenvatinib in vitro, leading to reduced cell numbers and altered TSP-1/CD47 expression.
Conclusions:
- Pericytes are a key component of the ATC tumor microenvironment.
- Lenvatinib demonstrates inhibitory effects on ATC cells, particularly in the presence of pericytes.
- Pericyte abundance may serve as a prognostic marker and influence therapeutic strategies for ATC.
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