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The role of the senescent microenvironment on cancer initiating cells in the colon.

Award Number: U01AG077920
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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The role of the senescent microenvironment on cancer initiating cells in the colon. - PROJECT SUMMARY/ABSTRACT Advanced age is the single most significant risk factor for cancer. Although there are many plausible age-related mechanisms that mediate the increased risk for cancer in the elderly, functional evidence is lacking for the majority of these mechanisms. This proposal will focus on the role of the aged microenvironment, particularly senescence, in promoting the formation of colorectal cancer (CRC), which is a common age-related cancer in the U.S. It is well established that the majority of CRCs arise through the serial accumulation of mutations and epigenetic alterations in oncogenes and tumor suppressor genes in colon epithelial stem cells. However, our group and others have found cells with cancer-causing DNA alterations (e.g. oncogenic KRAS and TP53) in the histologically normal colon mucosa of people, which suggests that the DNA alterations alone are not sufficient to drive the complete CRC formation process. Our group has recently shown that a senescent normal colon tissue microenvironment can promote the neoplastic behavior of colon epithelial cells ex vivo. We found increased senescent fibroblasts in the colons of the elderly and of people at high risk for CRC. We found that certain senescence associated secretory phenotype (SASP) factors produced by senescent fibroblasts can induce cancer hallmark behaviors through the activation of oncogenic signaling pathways. Based on our preliminary data we hypothesize that senescent fibroblasts in older people and the accompanying specific Senescence Associated Secretory Phenotype (SASP) secreted proteins promote the tumorigenesis of colon epithelial cells that have acquired age-related oncogenic mutations, which we have defined as cancer-initiating cells. To provide direct functional evidence to test this hypothesis, we propose the following Specific Aims: AIM 1A. To determine whether senescent fibroblasts can promote the survival and/or transformation of colon cancer initiating cells in ex vivo and in vivo organoid model systems. AIM 1B. To determine the necessary and sufficient role of specific cancer-associated SASP factors produced by the senescent fibroblasts in cancer formation. AIM 2. To determine whether a senescent tissue microenvironment is necessary for the survival and clonal expansion of mutant APC and mutant KRAS cancer-initiating cells using a well characterized CRC mouse model, the inducible Villin-Cre;Apcflx/flx; KrasLSL-G12D (AK) mice, with two approaches: AIM 2A: a pharmacological approach using the senomorphic drug rapamycin and the senolytic drug treatment DNQ (dasatinib and quercetin) AIM 2B: a genetic approach using the p16-3MR transgenic model, which allows the inducible ablation of senescent cells.


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 = $464,341 )
2025	2025	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	6	8/15/2025	NON-COMPETING CONTINUATION	$464,341
														Subtotal = $464,341

Issue Date FY: 2024 ( Subtotal = $481,298 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	5	7/19/2024	NON-COMPETING CONTINUATION	$481,298
														Subtotal = $481,298

Issue Date FY: 2023 ( Subtotal = $672,362 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	003	4	9/4/2023	SUPPLEMENT FOR EXPANSION	$183,278
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	002	4	8/14/2023	NON-COMPETING CONTINUATION	$489,084
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	3	4/3/2023	NON-COMPETING CONTINUATION	$0
2023	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	3	12/13/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $672,362

Issue Date FY: 2022 ( Subtotal = $496,221 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	006	3	8/31/2022	NON-COMPETING CONTINUATION	$496,221
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	002	2	7/18/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$69,415
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	004	2	8/17/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$161,323
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	003	1	8/17/2022	NEW	-$161,323
2022	2021	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	005	2	8/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	1	7/15/2022	NEW	-$69,415
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	4/22/2022	NEW	$0
														Subtotal = $496,221

Issue Date FY: 2021 ( Subtotal = $521,375 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	001	1	9/24/2021	NEW	$0
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Biology Research	000	1	9/21/2021	NEW	$521,375
														Subtotal = $521,375

Grand Total All Awards = $2,635,597

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The role of the senescent microenvironment on cancer initiating cells in the colon.

Award Number: U01AG077920

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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