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.