Pharmacological and dietary inhibition of a novel metabolic-epigenetic crosstalk in head and neck cancer - PROJECT SUMMARY Head and Neck Squamous Cell Carcinoma (HNSCC) is an aggressive malignancy derived from stratified squamous epithelium of the oral cavity. Leukoplakia is a premalignant condition and is recognized as the precursor lesion of HNSCC. During leukoplakia-associated neoplastic evolution, benign squamous epithelium first becomes dysplasia, then carcinoma in situ, and finally progresses to invasive SCC. Therefore, leukoplakia serves as an ideal premalignant model for the investigation of the step-wise neoplastic evolution of oral squamous epithelial cells. However, our understanding of the molecular mechanisms promoting leukoplakia- associated neoplasia remains quite limited. This shortcoming is largely due to viable and valid human models representing this unique pathological transition have been lacking. To address this key challenge, we have developed two independent, cross-species organoid systems modeling the step-wise neoplastic evolution of HNSCC. Both metabolic reprogramming and epigenomic deregulation are cancer hallmarks. Here we have mapped a key mechanistic crosstalk between the methionine cycle and epigenomic reprogramming, through a novel cascade involving LAT1-methionine-EZH2. Specifically, we find that HNSCC exhibits the highest activity of this cascade among all human cancers. High LAT1 expression correlates with poor survival of HNSCC patients. Importantly, this cascade is indispensable for the survival and proliferation of HNSCC cells, representing a tumor-specific vulnerability. Notably, this novel LAT1-methionine-EZH2 cascade can be targeted by either pharmacological approaches or dietary intervention. These interesting and significant findings prompt us to hypothesize that the novel LAT1-methionine-EZH2 cascade functionally promotes both early precursor transformation and cancer development, representing a prominent actionable target for cancer prevention and treatment. To test this hypothesis, we will leverage our versatile premalignant and tumor organoid systems as well as animal models, to investigate the biological significance of the LAT1-methionine-EZH2 cascade during both the initial steps of oral neoplastic transformation and fully-established HNSCC tumors. We will establish the molecular basis of this pathway using advanced metabolomic profiling and epigenomic approaches such as Cut&Tag. We will perform preclinical evaluation of pharmacological and dietary blockade of this cascade, to rigorously assess both tumor-prevention and tumor-killing effect of candidate approaches. We will further develop LAT1-high vs LAT1-low organoid models to investigate whether LAT1 serves as a biomarker to predict cellular dependence on the LAT1-methionine-EZH2 axis. This study not only investigates fundamental cancer biology, but also has significant translational implications for both early intervention and treatment of HNSCC.
