With the help of medical research, the incidences and mortalities of many common cancers (e.g., those from breast, lung and colon cancers) are dropping significantly in US. However, as one of the deadliest malignancies, esophageal carcinoma (EAC) has strikingly risen in incidence (> 600% during the last four decades in USA), with the five-year survival of only 16%. Although Barrett’s esophagus (BE) has long been regarded as a precursor lesion of EAC, no effective preventive strategies is available. Better characterization of EAC pathogenesis and its evolution from BE is greatly needed to decrease the impact of this deadly cancer.