Abstract
Metastasis presents a significant challenge in head and neck squamous cell carcinoma (HNSC), profoundly impacting patient morbidity and mortality. This proof-of-concept study establishes patient-derived orthotopic xenografts (PDOXs) as an advanced preclinical model to investigate and address metastatic HNSC. Indeed, PDOXs demonstrate noteworthy histopathological and molecular fidelity to primary HNSC tumours. Contrary to the traditional subcutaneous xenografts, PDOXs authentically replicate local lymph node metastasis, mirroring the intricate site-specific cancer-stroma interaction and the disease progression in patients. Furthermore, genomic and transcriptomic analyses underscore the genetic accuracy and heightened resemblance of PDOXs to patient tumours. Notably, nuclear factor kappa-B (NF-κB)-signalling-induced inflammation emerges as a key driver of the metastatic process, unveiling an inflammatory signature with potential implications as a prognostic marker and therapeutic target. These findings underscore the pivotal role of the PDOX model in capturing the complex biology of HNSC, providing insights for precision-targeted therapies and enhancing patient outcomes.