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Background <p>Although tumor cell heterogeneity between the tumor center (TC) and invasion front (IF) of oral squamous cell carcinoma (OSCC) is well documented, the morphological, molecular, and functional characteristics of cancer-associated fibroblasts (CAFs) in these regions remain poorly understood.</p> Methods <p>We examined hematoxylin and eosin (H&amp;E)–stained OSCC sections to assess CAF morphology and correlation with patient prognosis. We then isolated paired CAFs from the tumor center (CAF<sup>TC</sup>) and invasion front (CAF<sup>IF</sup>) of four OSCC patients and compared their ECM-remodeling activity and pro-tumorigenic effects on OSCC cells. Furthermore, RNA sequencing identified differentially expressed genes between CAF<sup>TC</sup> and CAF<sup>IF</sup>. Finally, based on RNA-seq findings, we knocked down hyaluronan synthase 1 (HAS1) in CAF<sup>IF</sup> to evaluate its role in extracellular matrix (ECM) remodeling and tumor invasion.</p> Results <p>Compared to CAF<sup>TC</sup>, CAF<sup>IF</sup> exhibited a plump cell morphology and were associated with shorter disease-free survival. Functionally, CAF<sup>IF</sup> showed higher ECM-remodeling activity and more effective ability for promoting OSCC invasion and lymph node metastasis than CAF<sup>TC</sup>. RNA-seq identified HAS1 was significantly upregulated in CAF<sup>IF</sup>, promoting hyaluronic acid (HA) production and ECM remodeling. HAS1 knockdown in CAF<sup>IF</sup> diminished ECM remodeling and attenuated the ability of CAF<sup>IF</sup> to promoting OSCC invasion.</p> Conclusion <p>CAF<sup>IF</sup> with plump cell morphology showed pro-invasive abilities, driven in part by HAS1 overexpression and ECM remodeling, suggesting that targeting HAS1-driven ECM remodeling could be a promising therapeutic strategy.</p>

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HAS1high cancer associated fibroblasts located at the tumor invasion front zone promote oral squamous cell carcinoma invasion via ECM remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • Wanyong Jin,
  • Qiuya Yu,
  • Liyuan Yu,
  • Ting Zhou,
  • Xiren Wang,
  • Wanqiu Lu,
  • Xiaoxin Zhang,
  • Liang Ding,
  • Qingang Hu,
  • Yanhong Ni

摘要

Background

Although tumor cell heterogeneity between the tumor center (TC) and invasion front (IF) of oral squamous cell carcinoma (OSCC) is well documented, the morphological, molecular, and functional characteristics of cancer-associated fibroblasts (CAFs) in these regions remain poorly understood.

Methods

We examined hematoxylin and eosin (H&E)–stained OSCC sections to assess CAF morphology and correlation with patient prognosis. We then isolated paired CAFs from the tumor center (CAFTC) and invasion front (CAFIF) of four OSCC patients and compared their ECM-remodeling activity and pro-tumorigenic effects on OSCC cells. Furthermore, RNA sequencing identified differentially expressed genes between CAFTC and CAFIF. Finally, based on RNA-seq findings, we knocked down hyaluronan synthase 1 (HAS1) in CAFIF to evaluate its role in extracellular matrix (ECM) remodeling and tumor invasion.

Results

Compared to CAFTC, CAFIF exhibited a plump cell morphology and were associated with shorter disease-free survival. Functionally, CAFIF showed higher ECM-remodeling activity and more effective ability for promoting OSCC invasion and lymph node metastasis than CAFTC. RNA-seq identified HAS1 was significantly upregulated in CAFIF, promoting hyaluronic acid (HA) production and ECM remodeling. HAS1 knockdown in CAFIF diminished ECM remodeling and attenuated the ability of CAFIF to promoting OSCC invasion.

Conclusion

CAFIF with plump cell morphology showed pro-invasive abilities, driven in part by HAS1 overexpression and ECM remodeling, suggesting that targeting HAS1-driven ECM remodeling could be a promising therapeutic strategy.