GOT1 Inhibition Induces Extracellular Matrix Remodeling in Pancreatic Cancer

Using tumor tissue engineering, we recreated pancreatic cancer and found that inhibiting glutamic‐oxaloacetic transaminase 1 (GOT1) induces extracellular matrix remodeling and secretome rewiring, as well as promotes cell death. ABSTRACT Pancreatic cancer cells rely on glutamine to sustain their survival in the stiff and poorly vascularized tumor microenvironment (TME). Inhibiting glutamic‐oxaloacetic transaminase 1 (GOT1) is a strategy to target glutamine metabolism and impair cancer cell functions. However, it remains unclear how cellular and extracellular elements of the TME respond to GOT1 inhibition. We engineered a pancreatic TME model ‘on a dish’ and recreated the metabolic interactions. Stromal cells remodeled the extracellular matrix and upregulated metabolic programs, including glutamine metabolism, oxidative phosphorylation, and central carbon metabolism. Cell responses to GOT1 inhibition were modulated by TME elements, with reductions in cell viability and proliferation occurring only under tissue‐like conditions. GOT1 inhibition altered matrix organization by upregulating different matrix‐related proteins, while it did not enhance cell responses to cytotoxic drugs. Our findings uncover the metabolic crosstalk within the TME and show that metabolism‐targeting treatments directly impact stromal elements of pancreatic cancer. Using tumor tissue engineering, we recreated pancreatic cancer and found that inhibiting glutamic-oxaloacetic transaminase 1 (GOT1) induces extracellular matrix remodeling and secretome rewiring, as well as promotes cell death. ABSTRACT Pancreatic cancer cells rely on glutamine to sustain their survival in the stiff and poorly vascularized tumor microenvironment (TME). Inhibiting glutamic-oxaloacetic transaminase 1 (GOT1) is a strategy to target glutamine metabolism and impair cancer cell functions. However, it remains unclear how cellular and extracellular elements of the TME respond to GOT1 inhibition. We engineered a pancreatic TME model ‘ on a dish ’ and recreated the metabolic interactions. Stromal cells remodeled the extracellular matrix and upregulated metabolic programs, including glutamine metabolism, oxidative phosphorylation, and central carbon metabolism. Cell responses to GOT1 inhibition were modulated by TME elements, with reductions in cell viability and proliferation occurring only under tissue-like conditions. GOT1 inhibition altered matrix organization by upregulating different matrix-related proteins, while it did not enhance cell responses to cytotoxic drugs. Our findings uncover the metabolic crosstalk within the TME and show that metabolism-targeting treatments directly impact stromal elements of pancreatic cancer. Advanced Science, EarlyView.