Differential squamous cell fates elicited by NRF2 gain-of-function versus KEAP1 loss-of-function

Clinical evidence has revealed that high-level activation of NRF2 caused by somatic mutations in NRF2 is frequently detected in esophageal squamous cell carcinoma (ESCC), whereas that by somatic mutations in KEAP1, a negative regulator of NRF2, is not. Here, we challenged to generate a mouse model of NRF2-activated ESCC using the cancer-derived NRF2L30F mutation and cancer-driver mutant Trp53R172H. Concomitant expression of NRF2L30F and Trp53R172H induced proliferation of squamous cell epithelia and resulted in NRF2-activated ESCC-like lesions. In contrast, while squamous cell-specific deletion of KEAP1 induced similar NRF2 hyper-activation, the loss-of-KEAP1 combined with Trp53R172H did not elicit the proliferation and formation of ESCC-like lesions. Instead, KEAP1-deleted cells disappeared from the esophageal epithelium over time by cell competition. These findings provide insights into the observation that somatic mutations are more frequently observed in NRF2 than in KEAP1, and the mouse model developed here will be instrumental in elucidating the mechanistic basis leading to NRF2-activated ESCC.