Wednesday, September 17, 2025 9/17/2025

Master regulator transcription factors promote esophageal neoplastic evolution

Award Number: R37CA237022
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Master regulator transcription factors promote esophageal neoplastic evolution - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $764,836 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	000	6	8/25/2025	EXTENSION WITH OR WITHOUT FUNDS	$764,836
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	001	5	9/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $764,836

Issue Date FY: 2024 ( Subtotal = $370,711 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Biology Research	000	5	5/9/2024	NON-COMPETING CONTINUATION	$370,711
														Subtotal = $370,711

Issue Date FY: 2023 ( Subtotal = $382,417 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Biology Research	000	4	5/11/2023	NON-COMPETING CONTINUATION	$382,417
														Subtotal = $382,417

Issue Date FY: 2022 ( Subtotal = $406,472 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Biology Research	003	3	6/15/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$308,639
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Cancer Biology Research	001	3	5/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$406,472
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	2	5/20/2022	NON-COMPETING CONTINUATION	$0
2022	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Cancer Biology Research	002	2	6/15/2022	NON-COMPETING CONTINUATION	-$308,639
														Subtotal = $406,472

Issue Date FY: 2021 ( Subtotal = $380,154 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	2	5/13/2021	NON-COMPETING CONTINUATION	$380,154
														Subtotal = $380,154

Issue Date FY: 2020 ( Subtotal = $395,480 )
2020	2020	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Cancer Biology Research	000	1	6/26/2020	NEW	$395,480
														Subtotal = $395,480

Grand Total All Awards = $2,700,070

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Master regulator transcription factors promote esophageal neoplastic evolution

Award Number: R37CA237022

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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