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Understanding adenoma progression: Interplay among tissue microenvironment, clonal architecture, and gut microbiome

Award Number: U54CA274374
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Understanding adenoma progression: Interplay among tissue microenvironment, clonal architecture, and gut microbiome - SUMMARY Colorectal cancer (CRC) affects ~145,000 people/year in the US and is the 3rd most common cause of cancer related deaths. CRC arises from early lesions that are pre-cancerous; these early lesions are colon adenomas and serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the CRC precancerous lesions and progress to CRC via an early adenomaàadvanced adenomaàCRC sequence. In light of the well characterized clinical natural history of adenomas, we plan to study them as early lesions and to determine the mechanisms involved in the formation and progression of early precancerous lesions. Notably, only a few early adenomas will progress to advanced adenomas (AA) and even fewer will progress to CRC. Our group and others have shown that mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases. There are likely multiple adenoma nonautonomous mechanisms that cooperate with the DNA alterations in the adenomas to cause progression, and these mechanisms are likely operative in discrete subsets of affected individuals. We and others have observed alterations, such as tissue senescence, high cancer driver gene mutation loads, aberrant DNA methylation patterns, and dysbiotic gut microbiomes, in the normal colon of people with advanced adenomas and CRC patients. We have termed normal colons with these features “primed colons” and propose that these features are plausible mechanisms that affect adenoma initiation and progression. Based on these observations and our prior studies, we hypothesize that early lesion progression requires a suite of hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g. cancer driver gene mutations) and adenoma nonautonomous factors from the “primed colon” or adenoma microenvironment. Our proposed studies will integrate basic and translational cancer research Projects to iteratively examine the direct causal relationships and interactions of adenomas, the colon “primed” microenvironment, and host- systemic factors as “co-organizers” of adenoma initiation and/or progression. The Specific Aims are: Aim 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomas from advanced adenomas and that regulate nonadvanced adenoma progression. (Projects 1 and 2) Aim 2) To determine the adenoma nonautonomous factors from the “primed” colon and from the adenoma microenvironment that associate with advanced human colon adenomas and regulate adenoma progression. These factors will include the following “primed” colon states: 1. senescence state; 2. cancer driver gene mutation burden; 3. gut microbiome state; 4. colon methylome, and 5. colon immune activity state. (Projects 1-3) Aim 3)To determine how adenoma autonomous and nonautonomous factors from the adenoma microenvironment and the “primed” colon cooperate to drive adenoma formation and progression.(Projcts 1-3)


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 = $1,934,892 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	003	4	9/9/2025	NON-COMPETING CONTINUATION	$1,579,708
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Centers Support Grants	004	4	9/12/2025	SUPPLEMENT FOR EXPANSION	$100,184
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	005	4	9/16/2025	SUPPLEMENT FOR EXPANSION	$255,000
2025	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	002	3	6/24/2025	NON-COMPETING CONTINUATION	$0
2025	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	000	3	10/15/2024	SUPPLEMENT FOR EXPANSION	$0
2025	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	001	3	11/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,934,892

Issue Date FY: 2024 ( Subtotal = $2,286,491 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	002	3	9/5/2024	NON-COMPETING CONTINUATION	-$83,004
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	001	3	9/4/2024	NON-COMPETING CONTINUATION	$1,660,085
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	006	3	9/13/2024	SUPPLEMENT FOR EXPANSION	$176,000
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Centers Support Grants	003	3	9/9/2024	SUPPLEMENT FOR EXPANSION	$100,184
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	004	3	9/10/2024	SUPPLEMENT FOR EXPANSION	$255,000
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	005	3	9/12/2024	SUPPLEMENT FOR EXPANSION	$178,226
2024	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	000	2	1/9/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $2,286,491

Issue Date FY: 2023 ( Subtotal = $1,782,897 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	001	2	9/8/2023	NON-COMPETING CONTINUATION	$1,607,986
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	002	2	9/11/2023	SUPPLEMENT FOR EXPANSION	$174,911
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	000	1	11/2/2022	NEW	$0
														Subtotal = $1,782,897

Issue Date FY: 2022 ( Subtotal = $1,692,618 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Control	000	1	9/20/2022	NEW	$1,692,618
														Subtotal = $1,692,618

Grand Total All Awards = $7,696,898

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Understanding adenoma progression: Interplay among tissue microenvironment, clonal architecture, and gut microbiome

Award Number: U54CA274374

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/20/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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