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<p>Given that head and neck squamous cell carcinoma (HNSCC) patients have poor survival outcomes, a better understanding of the therapeutic benefits of ionizing irradiation (IR), the major treatment modality besides surgery, is needed. A confounding factor is the immunosuppressive tumor microenvironment determined by tenascin-C (TNC), a highly abundant extracellular matrix molecule upregulated by IR. We investigated the roles of TNC on radio-induced tumor regression in a murine oral HNSCC model expressing or lacking TNC. While tumors in a TNC-expressing host were radiosensitive, they were radioresistant in TNC genetically depleted mice. We identified fibroblast reticular cells (FRCs) as critical regulators. TNC plays a compartmentalized and dual role in regulating tumor radiosensitivity with a detrimental role in the tumor stroma opposed to an essential role in the tumor-draining lymph nodes. This is relevant as a high FRC signature and high TNC levels together correlate with shorter HNSCC patient survival. TNC-expressing FRCs may be an excellent novel target to improve radiotherapy-induced tumor eradication, as our TNC targeting MAREMO peptide reduced tumor cell numbers and plasticity upon IR.</p>

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Tenascin-C orchestrates radiotherapy-induced head and neck tumor regression

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

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  • Thomas Loustau,
  • Ioanna Mitrentsi,
  • Nuohan Wang,
  • Caroline Spenlé,
  • Alexia Pavlidaki,
  • Thibaud Tranchant,
  • Gilles Riegel,
  • Akhil Venu,
  • Rime Oueidat,
  • Manuel Koch,
  • Marion Dumas,
  • Fanny Wack,
  • Aurelie Hirschler,
  • Christine Carapito,
  • Nicodème Paul,
  • Raphael Carapito,
  • Matthias Mörgelin,
  • Uwe Hansen,
  • Joyce Azzi,
  • Lucie Aubergeon,
  • Nathalie Salomé,
  • Sayda Dhaouadi,
  • Pierre Grenot,
  • Balkiss Bouhaouala-Zahar,
  • Simona La Cioppa,
  • Philippe Oertle,
  • Valerio Izzi,
  • Marija Plodinec,
  • Georges Noel,
  • Hélène Burckel,
  • Gertraud Orend

摘要

Given that head and neck squamous cell carcinoma (HNSCC) patients have poor survival outcomes, a better understanding of the therapeutic benefits of ionizing irradiation (IR), the major treatment modality besides surgery, is needed. A confounding factor is the immunosuppressive tumor microenvironment determined by tenascin-C (TNC), a highly abundant extracellular matrix molecule upregulated by IR. We investigated the roles of TNC on radio-induced tumor regression in a murine oral HNSCC model expressing or lacking TNC. While tumors in a TNC-expressing host were radiosensitive, they were radioresistant in TNC genetically depleted mice. We identified fibroblast reticular cells (FRCs) as critical regulators. TNC plays a compartmentalized and dual role in regulating tumor radiosensitivity with a detrimental role in the tumor stroma opposed to an essential role in the tumor-draining lymph nodes. This is relevant as a high FRC signature and high TNC levels together correlate with shorter HNSCC patient survival. TNC-expressing FRCs may be an excellent novel target to improve radiotherapy-induced tumor eradication, as our TNC targeting MAREMO peptide reduced tumor cell numbers and plasticity upon IR.