Tenascin-C orchestrates radiotherapy-induced head and neck tumor regression
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.
Authors
- Thibaud Tranchant (ORCID: https://orcid.org/0000-0002-8539-3186)
- Pierre Grenot (ORCID: https://orcid.org/0000-0003-3991-753X)
- Gertraud Orend (ORCID: https://orcid.org/0000-0003-2522-1195)
- Valerio Izzi (ORCID: https://orcid.org/0000-0002-9960-4917)
- Nathalie Salomé (ORCID: https://orcid.org/0000-0002-0349-0258)
- Sayda Dhaouadi (ORCID: https://orcid.org/0000-0001-7606-1895)
- Marija Plodinec (ORCID: https://orcid.org/0000-0002-5260-8179)
- Uwe Hansen (ORCID: https://orcid.org/0000-0001-8519-8228)
- Aurélie Hirschler (ORCID: https://orcid.org/0000-0001-5066-6263)
- Gilles Riegel (ORCID: https://orcid.org/0000-0003-4013-8234)
- Caroline Spenlé (ORCID: https://orcid.org/0000-0002-6353-3109)
- Raphaël Carapito (ORCID: https://orcid.org/0000-0002-7036-442X)
- Ioanna Mitrentsi
- Alexia Pavlidaki
- Lucie Aubergeon (ORCID: https://orcid.org/0000-0002-3459-7904)
- Christine Carapito (ORCID: https://orcid.org/0000-0002-0079-319X)
- Thomas Loustau (ORCID: https://orcid.org/0000-0003-4662-5228)
- Hélène Burckel (ORCID: https://orcid.org/0000-0002-9612-5806)
- Nicodème Paul (ORCID: https://orcid.org/0000-0003-4680-3012)
- Simona Y. La Cioppa
- Fanny Wack (ORCID: https://orcid.org/0000-0001-9300-725X)
- Akhil Venu
- Matthias Mörgelin
- Balkiss Bouhaouala-Zahar
- Manuel Koch
- Georges Noel
- Nuohan Wang
- Rime Oueidat
- Marion Dumas
- Philippe Oertle
- Joyce Azzi
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Institut Pluridisciplinaire Hubert Curien (FR)
- Institut de Cancérologie Strasbourg (FR)
- Multidisciplinary Digital Publishing Institute (Switzerland) (CH)
- University Hospital Münster (DE)
- Immunologie, Immunopathologie et Chimie Thérapeutique (FR)
- Institut Pasteur de Tunis (TN)
- Laboratoire Image, Ville, Environnement (FR)
- University Hospital Cologne (DE)
- Hôpital Civil, Strasbourg (FR)
- Université de Strasbourg (FR)
- University of Oulu (FI)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1038/s44321-026-00406-8
- Primary Topic
- Cell Adhesion Molecules Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Institut National Du Cancer