Dissecting the impact of epithelial stem cell niches on oral cancer heterogeneity

The oral epithelium is a unique tissue with a high degree of structural heterogeneity and distinct microenvironments (niches). However, the molecular mechanisms underlying the site-specific proliferation and differentiation of oral epithelial stem cells (OESCs) remain poorly understood. Oral squamous cell carcinoma (OSCC), one of the most common oral cancers, is a heterogeneous cancer type. Occurrences of metastatic lesions and treatment response differ from oral site to site, indicating a causal link to the heterogeneous nature of distinct OESC pools. In the OralNiche project, we will for the first time systematically and comprehensively characterise the OESC pools, dissect key mechanisms underlying oral epithelial site-specificity and define their contribution to OSCC heterogeneity. To achieve this, we will combine novel mouse models and patient material with cutting-edge methodology, including whole mount imaging, single-cell sequencing and organoids. Initially, we will profile the proliferative activities of OESCs and explore how stemness is regulated within defined niches in homeostasis, OSCC and chemotherapy-induced mucositis. Subsequently, we will functionally assess cellular cues that modulate stemness in the oral epithelia and generate a comprehensive single-cell atlas of OESCs and their cellular niches. Lastly, using OSCC patient material, we will validate key observations to define potential new biomarkers and therapeutic targets. In summary, this multidisciplinary approach will reveal how the distinct OESC pools maintain homeostasis, and how they respond to challenges, such as mucositis and OSCC. OralNiche will deliver new knowledge on the impact of tissue site-specificity on tumour heterogeneity and therapy response, which will have significant implications for OSCC patients. Moreover, the knowledge gained and the technological advances proposed will be applicable to other tissues and tumour types and thus provide a model approach in cancer research.