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.
Invasive ductal carcinoma of the breast (IDC) is very common and is associated with poor outcomes making this disease a major public health issue. We propose to study the metabolic interactions between different cells in these tumors to determine if this drives aggressive cancer. The discovery of new metabolic mechanisms that promote aggressive disease may enable us to better predict outcomes and how to overcome this with targeted drugs.
