EPiTOME-M · Epigenetic Profiling and Telomere-Orchestrated Mechanisms in HPV+ Oropharyngeal Cancer

HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC) is a rapidly rising, clinically distinct subtype of head and neck cancer. Despite favourable prognosis, 1/3rd of patients relapse and 5–13% develop metastases within 3 years, reflecting marked interpatient and intra-tumoral heterogeneity and thus impacting treatment response. EPiTOME-M aims to address this challenge by identifying the cell of origin and dissecting epigenetic mechanisms driving heterogeneity and immune evasion. Current studies rely on bulk sequencing, which mask cell-type–specific signals and spatial complexity. I will apply sciMET-seq, a single-cell DNA methylation technology to create reference methylomes from normal tonsil and HPV+ OPSCC tissues, to identify lineage-specific epigenetic signatures. Building on this, I will map G-quadruplex (G4) structures—non-canonical DNA elements known to modulate methylation—within differentially methylated regions and test their functional impact using CRISPRi in HPV˖ OPSCC cell lines. Additionally, I will use patient-derived organoids to examine how telomere length influences the tumour immune microenvironment. This multidisciplinary approach—combining epigenomics, telomere biology, and immunology—will yield mechanistic insights into tumour heterogeneity and immune modulation, enabling novel biomarker discovery and precision stratification in HPV˖ OPSCC. The project will foster a two-way knowledge exchange between me and the host institutions, RCSI and secondment host KU Leuven. This includes expertise in DNA methylation and biomarker development, clinical insight and sample access (RCSI), telomere biology expertise (my contribution), and training in single-cell genomics (KU Leuven). Ultimately, by integrating these strengths, the fellowship will empower me to address a critical question in HPV+ OPSCC and establish a strong, independent research profile at the interface of telomere biology, epigenomics, and oncology.