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Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast

Award Number: R37CA234239
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/11/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast - Project Summary/Abstract: Outcomes in breast invasive ductal carcinoma (IDC) are poor. Our project focuses on the role of metabolic abnormalities driving aggressive cancer and how inflammation and oxidative stress regulate IDC aggressiveness via altered metabolism. Tumor cells in IDC frequently use one of two metabolic pathways: glycolysis with glucose catabolism to lactate and mitochondrial oxidative phosphorylation (OXPHOS). Altered metabolism with coupling based on release and uptake of metabolites between different cells in the tumor microenvironment is a feature of IDC. However, it is not known if metabolic coupling induces cancer aggressiveness. Targeting tumor metabolism may also be an effective way of treating IDC and allow us to develop new prognostic and predictive biomarkers. Multiple metabolic compartments are linked via inflammation, glycolysis and shuttles of lactate. Fibroblasts, which are the most common non-cancer cells in IDC tumors, have low OXPHOS, high glycolysis, high expression of lactate exporters, and high oxidative stress. Conversely, the carcinoma cells have high expression of transporters involved in the uptake of lactate, high OXPHOS and low glycolysis. We have identified high TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in IDC carcinoma cells as a driver of tumor microenvironment metabolic coupling. TIGAR reduces glycolytic flux as a fructose-2,6 bisphosphatase enzyme. Phospho-fructo-kinase 1 (PFK1) activity, which is a rate limiting step in glycolysis, is positively allosterically regulated by fructose 2,6 bisphosphate (Fru-2,6-P2). Hence, TIGAR reduces glycolytic flux via reduced PFK1 activity. Our overall hypothesis is that tumor microenvironment metabolic coupling, induced by TIGAR, is sufficient to induce carcinoma cell proliferation and resistance to cell death and that tumor microenvironment metabolic uncoupling will overcome tumor aggressiveness. We aim to use this knowledge on tumor microenvironment metabolic coupling to discover metabolic mechanisms of IDC aggressiveness. In Aim 1, we will test the hypothesis that metabolic coupling induced by TIGAR is sufficient to promote aggressive IDC. In Aim 2 we will test the hypothesis that inflammatory signaling is a driver of TIGAR-induced metabolic coupling and aggressiveness. Finally in Aim 3 we will test the hypothesis that oxidative stress is a driver of TIGAR- induced metabolic coupling and aggressiveness. In summary, understanding how metabolic interactions between different cells in IDC tumors drive aggressiveness may provide opportunities to develop novel therapeutics for IDC.


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 = $321,167 )
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	002	6	4/21/2025	EXTENSION WITH OR WITHOUT FUNDS	$29,073
2025	2025	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	6	1/9/2025	EXTENSION WITH OR WITHOUT FUNDS	$321,167
2025	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	5	4/21/2025	NON-COMPETING CONTINUATION	-$29,073
														Subtotal = $321,167

Issue Date FY: 2024 ( Subtotal = $339,008 )
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	5	4/18/2024	NON-COMPETING CONTINUATION	$17,843
2024	2024	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	5	12/1/2023	NON-COMPETING CONTINUATION	$321,165
														Subtotal = $339,008

Issue Date FY: 2023 ( Subtotal = $349,713 )
2023	2023	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	4	2/6/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2022 ( Subtotal = $356,850 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	3	6/22/2022	NON-COMPETING CONTINUATION	$35,685
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	3	11/18/2021	NON-COMPETING CONTINUATION	$321,165
														Subtotal = $356,850

Issue Date FY: 2021 ( Subtotal = $218,946 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	2	11/10/2020	NON-COMPETING CONTINUATION	$339,007
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	002	2	1/22/2021	NON-COMPETING CONTINUATION	$17,843
2021	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	003	1	4/2/2021	SUPPLEMENT FOR EXPANSION	-$137,904
2021	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	1	11/18/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $218,946

Issue Date FY: 2020 ( Subtotal = $512,850 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	000	1	12/11/2019	NEW	$356,850
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	1	9/21/2020	SUPPLEMENT FOR EXPANSION	$156,000
														Subtotal = $512,850

Grand Total All Awards = $2,098,534

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Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast

Award Number: R37CA234239

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/11/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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