PROJECT SUMMARY
Esophageal adenocarcinoma (EAC) is one of the deadliest malignancies, and its incidence has strikingly
increased 6-8 fold in Western countries (including the United States, UK and several European countries) over
the past 4 decades. Despite new insights gained from recent genomic analyses, meaningful therapeutic
improvements have not occurred and the 5-year survival of EAC has remained extremely low (~20%). Therefore,
alternative research approaches, including advanced epigenomic studies, are desperately needed to understand
the molecular basis of EAC for developing novel treatment regimens. Barrett’s esophagus (BE) is a premalignant
condition and is considered as the obligate precursor lesion of EAC. During Barrett’s esophagus-associated
neoplastic evolution, benign BE first becomes dysplastic and then progresses to EAC. Therefore, BE serves as
an ideal pre-malignant model for the investigation of the step-wise neoplastic evolution of esophageal epithelial
cells. However, our understanding of the molecular mechanisms promoting BEAN remains limited, with key
questions (e.g., the primary drivers for the malignant transformation of BE into EAC) still unaddressed.
We and others have shown that malignant transformation is accompanied by genome-wide gains and losses
of enhancers and super-enhancers, which are occupied and regulated by upstream master regulator
transcription factors (MRTFs). Indeed, our recent studies demonstrated profound alterations in both enhancer
usage and MRTF activity between normal gastroesophageal junction (NGEJ), BE and EAC samples. Particularly,
we have identified a set of EAC-specific MRTFs (ELF3, KLF5, GATA6, EHF). Pilot experiments have shown that
these 4 MRTFs co-occupy hundreds of EAC-specific enhancers and super-enhancers, indicating they may
regulate the EAC transcriptome. Moreover, these EAC-specific MRTFs are highly and uniquely expressed in
EAC compared with normal GEJ or BE samples and are functionally required for EAC cell proliferation.
Based on these findings, we hypothesize that EAC-specific MRTFs directly promote the malignant
transformation of BE cells by rewiring enhancers and super-enhancers across the epigenome, activating
signaling pathways and cellular processes essential for EAC development. We will test this hypothesis by
investigating the biological functions of MRTFs in human BE-derived 3D organoids. In addition, we will study the
mechanistic basis of the strong association between obesity and EAC by focusing on the regulatory loop of
MRTF and fatty-acid synthesis, which is the key downstream pathway identified by our preliminary data. These
investigations promise to establish primary driving forces of BE-associated neoplasia evolution and uncover
epigenomic mechanisms underlying esophagus transformation, which will fundamentally transform our insights
into the biology of esophageal cancer. More importantly, successful execution of this proposal may identify
potential avenue for the prevention and early intervention of EAC by targeting fatty-acid synthesis pathway in
the high-risk individuals (e.g., refractory and/or high-grade BE patients) with obese condition.