Monday, June 30, 2025 6/30/2025

Mechanisms of Serrated Colon Tumor Suppression

Award Number: R01CA190558
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Mechanisms of Serrated Colon Tumor Suppression - A lack of knowledge about the initiating moments of tumorigenesis leaves large gaps in our ability to detect cancer early or develop prevention strategies. Our primary objective of this competitive renewal is to define, in vivo, the immediate consequences of oncogenic mutations in BRAF during Serrated colon cancer formation. We will pursue these studies in colon stem cells, the presumed cell-of-origin of colon cancer. Work from the previous grant identified new genetic modifiers of Serrated tumorigenesis. We found that oncogenic BRAFV600E mutations paradoxically cause stem cells to differentiate rather than form tumors. However, when we inactivated tumor suppressor transcription factors CDX2 or SMAD4, Serrated tumorigenesis was markedly restored. Excitingly, we found that CDX2 and SMAD4 target genes can be used to stratify human patients for their susceptibility to Serrated tumors. The logical extension of these studies is to understand the molecular mechanisms that occur in stem cells in response to BRAFV600E mutations. We will focus on the downstream transcriptional effector of BRAF, pERK, and will leverage the genetic mouse models we created to address the following Aims: Our previous work found that the transcription factor CDX2 preserves mature colon identity, with fetal- specific chromatin regions opening upon CDX2-loss. We predict that pERK takes advantage accessible chromatin upon CDX2 loss. Aim 1 will compare the activity of pERK in wild type stem cells, and BRAFV600E or CDX2-mutant stem cells. State-of-the-art –omics approaches will allow first-of-a-kind measurements of pERK on stem cell chromatin, within hours after the BRAFV600E mutation is expressed from its endogenous locus. We will measure pERK binding activity, nuclear localization, and dynamic interactions with its protein partners. Aim 2 will look at the downstream gene regulatory consequences of the BRAFV600E mutation in stem cells lacking SMAD4. We previously demonstrated that SMAD4 loss predisposes mice to Serrated tumor formation, and SMAD4 is frequently mutated in human tumors. We predict that SMAD4 works with pERK to promote differentiation and suppress stem cell renewal. Epigenomics approaches will map pERK binding to the genome, and ATAC-seq and RNA-seq will profile changes to chromatin and the transcriptome. Finally, Aim 3 will functionally test a model that the injury/repair cycle in the colon can create a susceptible environment for BRAF-pERK to drive tumorigenesis, with the prediction that an altered transcriptional network is permissive to Serrated tumor formation during the injury/repair cycle. These studies would provide important pre-clinical models to help explain and test therapeutic strategies to suppress Serrated tumor initiation in humans. These studies are innovative with cutting edge -omics applications and GEMMs and significant in exploring untested mechanisms of oncogenic pERK in stem cells. Successful completion of these studies will have us poised to test therapeutic strategies for the prevention or early detection of Serrated Colon Cancer.


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 = $392,500 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	002	8	6/16/2025	NON-COMPETING CONTINUATION	$392,500
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	7	5/5/2025	NON-COMPETING CONTINUATION	$0
2025	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	7	6/16/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $463,140 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	7	5/9/2024	NON-COMPETING CONTINUATION	$372,875
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	7	8/2/2024	SUPPLEMENT FOR EXPANSION	$90,265
														Subtotal = $463,140

Issue Date FY: 2023 ( Subtotal = $392,500 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	6	6/8/2023	COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	10/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $343,925 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	5	6/17/2019	NON-COMPETING CONTINUATION	$343,925
														Subtotal = $343,925

Issue Date FY: 2018 ( Subtotal = $354,563 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	4	6/19/2018	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2017 ( Subtotal = $354,563 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	3	6/20/2017	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2016 ( Subtotal = $354,563 )
2016	2016	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	2	6/14/2016	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2015 ( Subtotal = $354,563 )
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	001	1	6/16/2015	NEW	$0
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Cause and Prevention Research	000	1	4/2/2015	NEW	$354,563
														Subtotal = $354,563

Grand Total All Awards = $3,010,317

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Mechanisms of Serrated Colon Tumor Suppression

Award Number: R01CA190558

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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