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Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival

Award Number: R01CA258697
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/10/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival - Project Summary Clear associations have been established between the food we eat and the development and progression of colorectal cancer (CRC). For example, the consumption of fructose increases the risk for CRC development and CRC-specific mortality. However, the mechanism underlying this association is unknown. We have shown that moderate daily exposure to oral high fructose corn syrup (HFCS, a mix of fructose and glucose) leads to larger and more aggressive intestinal adenomas in mice. These effects were absent in mice with genetic deficiency of ketohexokinase (KHK), the enzyme that converts fructose to fructose 1-phosphate (F1P). A metabolomic analysis of these tumors showed that F1P is highly abundant following HFCS exposure, and this increase correlates with a reduction in pyruvate kinase (PK) activity. Therefore, we hypothesize that F1P, the product of KHK, enhances tumor growth by acting as an allosteric inhibitor of PK to promote anabolic metabolism and cell survival. We will test this hypothesis using mouse physiology and organ metabolism, cell and human organoid culture, and recombinant protein biochemistry. In Aim 1, we will genetically and pharmacologically manipulate the M2 isozyme of PK (PKM2) in mice to interrogate its role as a mediator of HFCS-induced tumor growth. In Aim 2, we will define the mechanistic linkage between fructose exposure and cancer cell survival. We have found that cells in culture do not grow faster when exposed to fructose, however we observed a significant improvement in cell viability, especially under conditions of high cell density and hypoxia with fructose in the media. Therefore, we hypothesize that F1P inhibits PKM2 to promote hypoxic cell survival. We will test this hypothesis using cell and organoid culture models exposed to fructose and hypoxia. We will genetically and pharmacologically manipulate KHK and PKM2 expression and activity in these models to determine the specific effects of these proteins on cell metabolism and survival. In Aim 3, we will assess the effects of F1P on recombinant PK isoforms with a particular focus on PKM2. We hypothesize that fructose- derived F1P binds to and inhibits PKM2. We will perform biochemical activity and structural assays to determine the kinetic parameters and oligomeric state of PK isoforms in the presence of F1P. These experiments will reveal the molecular mechanisms of how F1P binds and inhibits PKM2. Together, these aims will change our fundamental understanding of how fructose alters tumor cell metabolism, define the fructose/F1P/PKM2 axis as a metabolic vulnerability of CRC, and provide pre-clinical evidence for PKM2 activators as a novel therapeutic modality to combat CRC.


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 = $482,108 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	000	6	1/6/2026	NON-COMPETING CONTINUATION	$482,108
														Subtotal = $482,108

Issue Date FY: 2025 ( Subtotal = $624,305 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	002	5	12/19/2024	NON-COMPETING CONTINUATION	$561,876
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	003	5	5/29/2025	NON-COMPETING CONTINUATION	$62,429
2025	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	12/9/2024	NON-COMPETING CONTINUATION	-$32,446
2025	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	001	4	12/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$32,446
														Subtotal = $624,305

Issue Date FY: 2024 ( Subtotal = $600,244 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Cancer Cause and Prevention Research	003	4	9/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$221,017
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Cause and Prevention Research	000	3	12/15/2023	NON-COMPETING CONTINUATION	$552,192
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Cause and Prevention Research	001	3	4/16/2024	NON-COMPETING CONTINUATION	$30,677
2024	2024	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Cause and Prevention Research	002	3	9/10/2024	NON-COMPETING CONTINUATION	-$203,642
														Subtotal = $600,244

Issue Date FY: 2023 ( Subtotal = $573,011 )
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	2	12/14/2022	NON-COMPETING CONTINUATION	$526,235
2023	2023	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	001	2	3/16/2023	NON-COMPETING CONTINUATION	$46,776
														Subtotal = $573,011

Issue Date FY: 2022 ( Subtotal = $563,602 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	1/10/2022	NEW	$563,602
														Subtotal = $563,602

Grand Total All Awards = $2,843,270

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Molecular Mechanisms of Fructose-induced Colorectal Cancer Cell Survival

Award Number: R01CA258697

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/10/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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