Résumé

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous malignancy in which human papillomavirus (HPV) status strongly influences therapeutic response. HPV+ tumors generally show greater sensitivity to treatment, whereas HPV- tumors are associated with poorer prognosis and increased resistance. This thesis investigated how HPV status shapes cellular adaptation to therapeutic stress, with a particular focus on therapy-induced senescence (TIS), autophagy and MMS19.
HPV- HNSCC cells developed a senescence-like phenotype following cisplatin or x-ray irradiation, whereas HPV+ cells showed limited induction. Silencing of the viral oncogenes E6 and E7 in HPV+ cells increased this phenotype, indicating that HPV actively modulates treatment-induced cellular responses. Proteomic analyses further identified autophagy- and lysosome-related pathways as major features distinguishing HPV- from HPV+ cells. Autophagy inhibition predominantly impaired proliferation and clonogenic survival in HPV- cells, supporting an HPV-dependent autophagy–senescence axis involved in treatment adaptation.
The second part of this thesis identified MMS19, a component of the cytosolic iron–sulfur cluster assembly machinery, as a potential determinant of HPV- HNSCC resistance. MMS19 was associated with poorer clinical outcome, while its silencing impaired proliferation and clonogenic survival, particularly in HPV- cells.
Together, these findings identify autophagy-dependent remodeling and MMS19-associated genome maintenance as potential vulnerabilities contributing to therapeutic resistance in HPV- HNSCC.

Jury

  • Prof. Anne-Catherine HEUSKIN (UNamur), Présidente
  • Prof. Carine MICHIELS (UNamur), Secrétaire
  • Prof. Francis RODIER (UMontreal)
  • Prof. Yves POUMAY (UNamur)
  • Prof. Anabelle DECOTTIGNIES (UCLouvain)
  • Prof. Marc THERRIEN (UMontreal)
  • Prof. Sue YOM (UCSF)