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Background <p>Cancer cells can acquire neuron-like characteristics (“neural mimicry”) to promote progression. However, the role of specific ion channel genes in Papillary Thyroid Carcinoma (PTC) and their clinical significance remains unclear.</p> Methods <p>We included transcriptomic data from 521 PTC patients in the TCGA cohort. A neuron-specific gene set was used to screen for potential targets. We constructed a prognostic model using LASSO logistic regression. To verify the cellular origin of the signature, we performed single-cell RNA sequencing (scRNA-seq) analysis on the GSE184362 dataset.</p> Results <p>We established an 8-gene signature involving <i>KCNN4</i>, <i>KCNN1</i>, <i>KCNT2</i>, <i>SNAP25</i>, <i>KCNK16</i>, <i>GABRG1</i>, <i>GABRG2</i>, and <i>GABRB2</i>. The model demonstrated good predictive performance for lymph node metastasis, with an AUC of 0.721 (95% CI 0.677–0.765). Single-cell analysis of seven integrated tumor samples (<i>N</i> = 65,744 cells) confirmed that <i>GABRB2</i> was specifically enriched in malignant thyrocytes (<i>EPCAM</i>+/<i>KRT18</i>+) at 200-fold higher detection rates than immune cells (20.0% vs. 0.1%, <i>P</i> ≈ 0), supporting tumor-intrinsic neural mimicry. High-risk patients showed immunosuppressive features with altered immune cell infiltration patterns.</p> Conclusion <p>This study identifies a malignant cell-intrinsic signature for predicting PTC prognosis. Validated by single-cell data, our findings suggest that targeting ion channels may represent a potential therapeutic strategy for modulating neuro-immune interactions in thyroid cancer, pending experimental validation.</p>

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Integrated bulk and single-cell RNA sequencing reveals a prognostic neuro-mimicry signature in papillary thyroid carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月22日

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  • Xinyu Liu,
  • Chengjin Mei,
  • Jifeng Tan,
  • Yanlan Liu,
  • Yuyao Liu,
  • Zhigang Zhou,
  • Jianfu Zhao

摘要

Background

Cancer cells can acquire neuron-like characteristics (“neural mimicry”) to promote progression. However, the role of specific ion channel genes in Papillary Thyroid Carcinoma (PTC) and their clinical significance remains unclear.

Methods

We included transcriptomic data from 521 PTC patients in the TCGA cohort. A neuron-specific gene set was used to screen for potential targets. We constructed a prognostic model using LASSO logistic regression. To verify the cellular origin of the signature, we performed single-cell RNA sequencing (scRNA-seq) analysis on the GSE184362 dataset.

Results

We established an 8-gene signature involving KCNN4, KCNN1, KCNT2, SNAP25, KCNK16, GABRG1, GABRG2, and GABRB2. The model demonstrated good predictive performance for lymph node metastasis, with an AUC of 0.721 (95% CI 0.677–0.765). Single-cell analysis of seven integrated tumor samples (N = 65,744 cells) confirmed that GABRB2 was specifically enriched in malignant thyrocytes (EPCAM+/KRT18+) at 200-fold higher detection rates than immune cells (20.0% vs. 0.1%, P ≈ 0), supporting tumor-intrinsic neural mimicry. High-risk patients showed immunosuppressive features with altered immune cell infiltration patterns.

Conclusion

This study identifies a malignant cell-intrinsic signature for predicting PTC prognosis. Validated by single-cell data, our findings suggest that targeting ion channels may represent a potential therapeutic strategy for modulating neuro-immune interactions in thyroid cancer, pending experimental validation.