Scholarlink

Background <p>Necrosis plays a pivotal role in the development of cisplatin resistance in metastatic neck lymph nodes of head and neck squamous cell carcinoma (HNSCC). However, the precise mechanisms underlying this association remain unclear.</p> Methods <p>We employed qPCR and DNA in situ hybridization to detect <i>Fusobacterium nucleatum</i> (<i>F. nucleatum</i>) in postoperative tissue specimens from node-positive HNSCC patients. Transcriptomic sequencing was performed to analyze gene expression changes in adipocytes following <i>F. nucleatum</i> co-culture. RNA and protein expression alterations were validated via qPCR, Western blot, and ELISA. Additionally, subcutaneous xenograft tumor models were utilized for in vivo validation.</p> Results <p><i>F. nucleatum</i> was found to preferentially colonize necrotic neck lymph nodes in HNSCC and infiltrate adjacent adipocytes. In vitro, <i>F. nucleatum</i> induced the formation of cancer-associated adipocytes via autocrine C-C motif chemokine ligand 2 (CCL2), which stimulated lipolysis and enhanced free fatty acid release. Paracrine CCL2 further drove glutathione accumulation and cisplatin resistance in HNSCC by upregulating solute carrier family 1 member 5 (SLC1A5) and solute carrier family 7 member 11 (SLC7A11). Notably, C-C chemokine receptor type 2 (CCR2) antagonist, RS504393, effectively reversed these <i>F. nucleatum</i>-mediated pro-tumor effects. In vivo studies further confirmed the role of <i>F. nucleatum</i>-reprogrammed adipocytes and the therapeutic potential of RS504393.</p> Conclusion <p>This study is the first to elucidate the crucial involvement of <i>F. nucleatum</i> in shaping cancer-associated adipocytes within the HNSCC microenvironment. <i>F. nucleatum</i>-reprogrammed adipocytes enhance cisplatin resistance via the CCL2-CCR2 axis, offering new therapeutic avenues to overcome chemotherapy resistance in necrotic neck lymph nodes.</p> Graphical Abstract <p><i>Fusobacterium nucleatum</i> (<i>F. nucleatum</i>) drives the transformation of adipocytes into a cancer-associated phenotype via autocrine CCL2 signaling. This process increases free fatty acid release to fuel tumor progression by enhancing lipolysis through the activation of CREB/HSL phosphorylation. Additionally, paracrine CCL2 from <i>F.&#xa0;nucleatum</i>-reprogrammed adipocytes upregulates SLC1A5 and SLC7A11 in head and neck squamous cell carcinoma (HNSCC), leading to glutathione (GSH) accumulation and cisplatin resistance. Pharmacological inhibition of CCR2 with RS504393 attenuates both cancer-associated adipocyte formation and cisplatin resistance, highlighting the therapeutic potential of targeting the CCL2-CCR2 axis in HNSCC.</p> <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Fusobacterium nucleatum-reprogrammed adipocytes promote tumor cisplatin resistance through the CCL2-CCR2 axis in the necrotic metastatic neck nodes of head and neck carcinoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月24日

查看全文
  • Feiran Li,
  • Xiaohui Yuan,
  • Hui-Ching Lau,
  • Yi Zhu,
  • Hongli Gong,
  • Huiying Huang,
  • Chi-Yao Hsueh,
  • Ming Zhang

摘要

Background

Necrosis plays a pivotal role in the development of cisplatin resistance in metastatic neck lymph nodes of head and neck squamous cell carcinoma (HNSCC). However, the precise mechanisms underlying this association remain unclear.

Methods

We employed qPCR and DNA in situ hybridization to detect Fusobacterium nucleatum (F. nucleatum) in postoperative tissue specimens from node-positive HNSCC patients. Transcriptomic sequencing was performed to analyze gene expression changes in adipocytes following F. nucleatum co-culture. RNA and protein expression alterations were validated via qPCR, Western blot, and ELISA. Additionally, subcutaneous xenograft tumor models were utilized for in vivo validation.

Results

F. nucleatum was found to preferentially colonize necrotic neck lymph nodes in HNSCC and infiltrate adjacent adipocytes. In vitro, F. nucleatum induced the formation of cancer-associated adipocytes via autocrine C-C motif chemokine ligand 2 (CCL2), which stimulated lipolysis and enhanced free fatty acid release. Paracrine CCL2 further drove glutathione accumulation and cisplatin resistance in HNSCC by upregulating solute carrier family 1 member 5 (SLC1A5) and solute carrier family 7 member 11 (SLC7A11). Notably, C-C chemokine receptor type 2 (CCR2) antagonist, RS504393, effectively reversed these F. nucleatum-mediated pro-tumor effects. In vivo studies further confirmed the role of F. nucleatum-reprogrammed adipocytes and the therapeutic potential of RS504393.

Conclusion

This study is the first to elucidate the crucial involvement of F. nucleatum in shaping cancer-associated adipocytes within the HNSCC microenvironment. F. nucleatum-reprogrammed adipocytes enhance cisplatin resistance via the CCL2-CCR2 axis, offering new therapeutic avenues to overcome chemotherapy resistance in necrotic neck lymph nodes.

Graphical Abstract

Fusobacterium nucleatum (F. nucleatum) drives the transformation of adipocytes into a cancer-associated phenotype via autocrine CCL2 signaling. This process increases free fatty acid release to fuel tumor progression by enhancing lipolysis through the activation of CREB/HSL phosphorylation. Additionally, paracrine CCL2 from F. nucleatum-reprogrammed adipocytes upregulates SLC1A5 and SLC7A11 in head and neck squamous cell carcinoma (HNSCC), leading to glutathione (GSH) accumulation and cisplatin resistance. Pharmacological inhibition of CCR2 with RS504393 attenuates both cancer-associated adipocyte formation and cisplatin resistance, highlighting the therapeutic potential of targeting the CCL2-CCR2 axis in HNSCC.