# Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast

> **NIH NIH R37** · THOMAS JEFFERSON UNIVERSITY · 2020 · $356,850

## Abstract

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.

## Key facts

- **NIH application ID:** 9887834
- **Project number:** 1R37CA234239-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Ubaldo Martinez Outschoorn
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $356,850
- **Award type:** 1
- **Project period:** 2019-12-11 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9887834

## Citation

> US National Institutes of Health, RePORTER application 9887834, Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast (1R37CA234239-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9887834. Licensed CC0.

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