PhD thesis defense in biological sciences by Karim Bouhjar

Study of treatment -induced senescence (TIS) in head and neck squamous cell carcinoma (HNSCC) according to the HPV status

Candidate

Karim Bouhjar

Promoters

Prof. Carine Michiels, UNamur, Department of biology, Laboratory of Cellular and Molecular Biology (URBC) 

Prof. Francis Rodier, Institut du Cancer de Montréal, Centre de recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM)

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)

Summary

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.