Kletzien, H.; Nguyen, N.-A.; Jena, S. G.; Buenrostro, J. D.; Wagers, A. J.

Oral squamous cell carcinomas (OSCC) account for ~90% of all oral malignancies and have devastating effects on overall health and quality of life. However, little is known about the early initiating events that drive the development of oral leukoplakia-like premalignant lesions (OPLs) and disease progression. Here, we create a mouse model of tobacco-related premalignant OSCC that takes into consideration its primary risk factors, including advancing age and male sex. This model notably recapitulates the age variant patterns of OSCC risk observed in humans, with a higher prevalence of oral premalignant lesions in older mice. In addition, by building a transcriptomic atlas with this system, we reveal genetic signatures associated with oncogenic progression in the tongue and buccal epithelium, and their resident somatic tissue stem cells. We also identify several novel transcriptomic signatures of premalignancy in OSCC, including enhanced immune response and expansion and dysregulation of head and neck tissue stem cells. These findings offer a new framework for investigating physiologically-relevant risk factors and drivers of OSCC and illuminate novel biological pathways underlying its pathology.