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Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.

Award Number: U01AG077921
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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Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering. - SUMMARY Aging is the greatest risk factor for cancer development, yet the physiological and molecular mechanisms underlying this relationship remain poorly understood. Undoubtedly, one contributing factor is time – i.e. the years or decades needed for a single cell to acquire sufficient mutations to trigger overt disease. However, other factors certainly play a role, including age-related changes in cell metabolism, DNA damage responses, immune cell function, and the abundance of senescent cells. While understanding how these factors influence tumorigenesis will reveal strategies to improve cancer intervention and treatment, facile models to study cancer in aged animals are lacking. Addressing this critical challenge, we incorporate somatic tissue engineering methods to introduce oncogenic mutations directly into the organs of aged mice, thereby obviating the time and costs of intercrossing and aging cohorts of multi-allelic genetically engineered mouse models (GEMMs). We have developed a range of such “non-germline GEMMs” (nGEMMs) of different target organs and cancer genotypes and shown that the resulting cancers recapitulate molecular and histological features of the corresponding human disease. We have also produced nGEMMs using aged mice and shown that the developing tumors have distinct immune infiltrates with different tumor surveillance capabilities. This proposal combines the unique capabilities of nGEMMs with state-of-the-art tissue analyses to assess the contribution of the aged environment to cancer manifestation in different organ contexts and compares results to settings in which dietary or genetic factors uncouple biological age from chronological age. Implementation of advanced single cell methods will produce a detailed picture of cell type and cell state differences in tumors developing in aged animals and perturbation studies will explore tumor cell intrinsic and extrinsic factors underlying age- related phenotypes. The proposed experiments will benefit from combining our expertise in cancer biology with that of Dr. Laura Niedernhofer, who has extensive experience in studying organismal aging. Our studies will establish broadly portable models for studying cancer in aged mice at a breadth and pace that was previously impossible and produce novel insights into how the epigenetic and physiological processes linked to age contribute to an increase in cancer incidence and/or progression.


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 = $507,444 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	5	8/18/2025	NON-COMPETING CONTINUATION	$507,444
2025	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	3/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $507,444

Issue Date FY: 2024 ( Subtotal = $517,800 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	4	7/12/2024	NON-COMPETING CONTINUATION	$517,800
														Subtotal = $517,800

Issue Date FY: 2023 ( Subtotal = $517,800 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	3	8/11/2023	NON-COMPETING CONTINUATION	$517,800
														Subtotal = $517,800

Issue Date FY: 2022 ( Subtotal = $517,800 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	2	8/31/2022	NON-COMPETING CONTINUATION	$517,800
2022	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	8/18/2022	NEW	$0
														Subtotal = $517,800

Issue Date FY: 2021 ( Subtotal = $537,050 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	1	9/21/2021	NEW	$537,050
														Subtotal = $537,050

Grand Total All Awards = $2,597,894

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Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.

Award Number: U01AG077921

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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