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Lenvatinib Targets PDGFR-β Pericytes and Inhibits Synergy With Thyroid Carcinoma Cells: Novel Translational Insights

Asumi Iesato1,2, Stephanie Li1,2, Giovanni Roti3

  • 1Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Experimental Pathology, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, MA, USA.

The Journal of Clinical Endocrinology and Metabolism
|July 24, 2021
PubMed
Abstract

Insights

This study reveals that increased pericyte abundance in papillary thyroid carcinoma (PTC) correlates with tumor aggressiveness. Lenvatinib effectively targets pericytes, enhancing PTC cell death and suggesting pericyte assessment for targeted therapy selection.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Pericytes express tyrosine kinases like platelet-derived growth factor receptor-β (PDGFR-β), influencing therapeutic responses.
  • Lenvatinib, a tyrosine kinase inhibitor, targets PDGFR-β and is used clinically.
  • Tumor progression and drug resistance can occur, especially with higher disease burden and metastasis.

Purpose of the Study:

  • Develop a gene signature to quantify pericyte abundance in thyroid cancer.
  • Assess the correlation between pericyte abundance and tumor aggressiveness.
  • Determine the efficacy of lenvatinib on thyroid pericytes and its synergy with thyroid carcinoma cells.

Main Methods:

  • Utilized a gene signature to estimate pericyte abundance in papillary thyroid carcinoma (PTC) and normal thyroid (NT) samples from TCGA.
  • Co-cultured thyroid-derived pericytes with PTC-derived cells to analyze paracrine signaling and lenvatinib response.
  • Investigated the effects of platelet-derived growth factor-BB on pericyte growth and signaling pathways.

Main Results:

  • Pericyte abundance was significantly higher in aggressive PTC subtypes (BRAFV600E with hTERT mutations) compared to normal thyroid or less aggressive PTC.
  • Identified upregulated pathways in pericytes related to tumor survival, immune modulation, and cell-cycle regulation.
  • Lenvatinib inhibited pericyte viability by targeting PDGFR-β signaling and significantly enhanced PTC cell death when pericytes were present.

Conclusions:

  • This study establishes a thyroid-specific model for lenvatinib's efficacy against pericytes, which hinders tumor growth.
  • Assessing pericyte abundance in PTC patients may be crucial for selecting appropriate targeted therapies like lenvatinib.
Keywords:
BRAFV600EPDGFR-βlenvatinibmicroenvironmentpericytethyroid cancer

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