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<p>Papillary thyroid carcinoma (PTC) undergoes dedifferentiation into aggressive poorly differentiated (PDTC) or anaplastic (ATC) carcinomas in 10–15% of cases, a process potentially driven by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), though their spatiotemporal dynamics remain poorly understood. Resveratrol (Res), a natural compound, has shown anticancer potential by promoting redifferentiation and apoptosis while inhibiting oncogenic signaling, suggesting utility in countering PTC dedifferentiation. Using spatial transcriptomics (10× Visium) on three surgical specimens, we obtained 14,191 high-quality spots annotated via UMAP and Leiden clustering into seven cell types, including CAFs, T cells, B cells, and others. Comparative gene expression and functional enrichment analyses revealed CAFs in poorly differentiated regions exhibited heightened glycolytic activity, correlated with ZFP57 upregulation and PKM2 induction. Glycolysis was validated through immunofluorescence, Seahorse assays, glucose/lactate measurements, and ZFP57-PKM2 reporter assays. CAF-conditioned media promoted PTC proliferation, invasion, and dedifferentiation while reducing radioiodine uptake in co-culture models. In xenografts, ZFP57 overexpression increased tumor growth and impaired radioiodine retention, whereas Res suppressed ZFP57, restored differentiation, enhanced radioiodine avidity, and inhibited glycolysis. Mechanistically, CAF-secretated lactate activated TGF-β/Smad2/3 signaling, fostering dedifferentiation and malignancy. Resveratrol reversed these effects by targeting ZFP57, normalizing CAF metabolism, and restoring PTC differentiation, indicating a promising therapeutic strategy against PTC progression.</p>

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Mechanism of cancer-associated fibroblast-driven thyroid cancer dedifferentiation via the ZFP57-PKM2 axis-mediated lactate secretion and therapeutic intervention with resveratrol​

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月27日

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  • Xiaoyu Ji,
  • Chengzhou Lv,
  • Xian Wu,
  • Hongpeng Wu,
  • Yuang Chang,
  • Qi Liu,
  • Wenwu Dong,
  • Jiapeng Huang,
  • Dalin Zhang,
  • Yao Diao,
  • Dapeng Sun,
  • Zhihong Wang,
  • Ping Zhang,
  • Wei Sun,
  • Hao Zhang

摘要

Papillary thyroid carcinoma (PTC) undergoes dedifferentiation into aggressive poorly differentiated (PDTC) or anaplastic (ATC) carcinomas in 10–15% of cases, a process potentially driven by cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME), though their spatiotemporal dynamics remain poorly understood. Resveratrol (Res), a natural compound, has shown anticancer potential by promoting redifferentiation and apoptosis while inhibiting oncogenic signaling, suggesting utility in countering PTC dedifferentiation. Using spatial transcriptomics (10× Visium) on three surgical specimens, we obtained 14,191 high-quality spots annotated via UMAP and Leiden clustering into seven cell types, including CAFs, T cells, B cells, and others. Comparative gene expression and functional enrichment analyses revealed CAFs in poorly differentiated regions exhibited heightened glycolytic activity, correlated with ZFP57 upregulation and PKM2 induction. Glycolysis was validated through immunofluorescence, Seahorse assays, glucose/lactate measurements, and ZFP57-PKM2 reporter assays. CAF-conditioned media promoted PTC proliferation, invasion, and dedifferentiation while reducing radioiodine uptake in co-culture models. In xenografts, ZFP57 overexpression increased tumor growth and impaired radioiodine retention, whereas Res suppressed ZFP57, restored differentiation, enhanced radioiodine avidity, and inhibited glycolysis. Mechanistically, CAF-secretated lactate activated TGF-β/Smad2/3 signaling, fostering dedifferentiation and malignancy. Resveratrol reversed these effects by targeting ZFP57, normalizing CAF metabolism, and restoring PTC differentiation, indicating a promising therapeutic strategy against PTC progression.