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Developmental control of chromatin states in cancer

Award Number: R01CA276663
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Developmental control of chromatin states in cancer - SUMMARY Ewing sarcoma, a cancer of the bone and soft tissue of children and young adults, remains a highly lethal cancer despite the use of aggressive chemotherapy, radiation, and surgery. The tumor is dependent on the development of a hybrid gene that brings together parts of two different genes, EWSR1 and FLI1, through chromosomal translocation or chromoplexy. The resulting EWS-FLI1 fusion oncoprotein acts as a transcriptional and chromatin regulator. Building from the work of our lab and others demonstrating that EWS-FLI1 gains neomorphic activity to regulates chromatin state at microsatellite coopted to become enhancers in tumor cells. However, we have shown that the activity and genomic targeting of EWS-FLI1 is influenced by the underlying epigenomic state of the cell. We demonstrated that primary and in vitro differentiated mesenchymal stem cells offer a chromatin state similar to that of Ewing sarcoma. We hypothesize that during stem cell differentiation a unique permissive chromatin state develops that enables EWS-FLI1. Further, we hypothesize that this permissive state is made up of chromatin regulators, characteristically modified histones and specific RNAs. In this project we will employ cancer cell (Aim 1) and stem cell developmental approaches (Aim 2) to identify the protein and RNA interactors and the posttranslational modifications of histones that create a favorable environment. We predict that critical features will be shared between both model systems. We will test the impact of these factors by evaluating the activity of EWS-FLI1 on chromatin states and transcription when these factors are modulated. The generation of Ewing sarcoma patient derived stem cells will enable us to evaluate the impact of EWS-FLI1 across the process of cellular differentiation. Integrated single cell analytics of chromatin accessibility and the transcriptome will enable direct evaluation of the impact of EWS-FLI1 on chromatin and, reciprocally, chromatin on EWS-FLI1. We will specifically study the biochemical interaction and functional relationship between EWS-FLI1 and the transcriptional regulator PAX7, one of the interactors identified during pilot experimentation.


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: 2026 ( Subtotal = $379,915 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$379,915
														Subtotal = $379,915

Issue Date FY: 2025 ( Subtotal = $424,710 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	3	3/4/2025	NON-COMPETING CONTINUATION	$382,238
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	3	5/22/2025	NON-COMPETING CONTINUATION	$42,472
														Subtotal = $424,710

Issue Date FY: 2024 ( Subtotal = $414,512 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$21,819
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	2	12/5/2023	NON-COMPETING CONTINUATION	$392,693
														Subtotal = $414,512

Issue Date FY: 2023 ( Subtotal = $411,481 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	1	12/23/2022	NEW	$411,481
														Subtotal = $411,481

Grand Total All Awards = $1,630,618

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Developmental control of chromatin states in cancer

Award Number: R01CA276663

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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