PhD defence R. (Reza) Ghadiri Rad

Below is a brief summary of the dissertation:

Tumor metastasis and the DNA damage response (DDR) are two fundamental features shaping cancer progression and therapeutic outcomes. Head and neck squamous cell carcinoma (HNSCC), a highly heterogeneous and aggressive malignancy, provides an ideal model to investigate how cellular plasticity and DDR heterogeneity contribute to metastasis and radio-resistance, processes that also underpin other solid tumors. Despite therapeutic advances, clinical improvements in HNSCC remain limited due to intra-tumoral heterogeneity and treatment failure, underscoring the need for mechanistic and functional insights at single-cell resolution.

This work integrates live-cell imaging, single-cell transcriptomics, and patient-derived models to bridge phenotypic behaviors with their molecular determinants. New functional single-cell selection and sequencing methods enable direct linking of cellular dynamics, such as invasiveness, migration, and DDR activity, to underlying gene expression and chromatin states. Using these approaches, distinct molecular programs governing aggressive phenotypes are identified, including epithelial‑to‑mesenchymal transition (EMT), TGFβ, NF‑κB, and cholesterol-regulated signaling in potential metastatic progression, as well as metabolic and epigenetic axes that shape DDR responses and ferroptosis susceptibility. Comparative analyses further reveal modality-specific effects of photon and proton irradiation, defining unique molecular pathways associated with radio-resistance or effective DNA damage control.