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Additional file 3: Supplementary Figure 3.PHGDH knockdown does not affect liver function. shPHGDH (N = 10) and shREN (N = 10) mouse serum was collected and analyzed by IDEXX (Liver Panel). (A) ALP – Alkaline phosphatase. (B) AST – aspartate transaminase. (C) ALT – alanine transaminase. (D) CK – creatine kinase. (E) – Total albumin. (E) Total bilirubin.

Additional file 2: Supplementary Figure 2. shPHGDH mice have poor knockdown in the spleen. Western blot analysis of PHGDH, GFP and HSP90 protein levels in spleen of shPHGDH and shREN mice. Mice were placed on a 200 ppm doxycycline diet for 8 months. ns, non-specific band.

Additional file 4: Supplementary Figure 4.PHGDH knockdown does not affect brain serine and lipids. (A) Brain serine quantities of 5- to 9-month-old shREN (N = 15) and shPHGDH (N = 14) mice. Quantities were normalized to mg of tissue. (B) Quantity of individual ceramides in the brain of 5- to 9-month-old shREN (N = 14) and shPHGDH (N = 15) mice. Quantities were normalized to mg of tissue. (C) Volcano plot of lipidomics analysis of shPHGDH (N = 15) brain compared to shREN (N = 15). Significant metabolites are in bold. Triacylglycerol species are indicated in red. (D) Individual TAG species in the brain of shPHGDH mice compared to shREN. Levels are normalized to shREN.

Additional file 1: Supplementary Figure 1.Validation of shRNAs for model development. NIH3T3 cells expressing Renilla or PHGDH-targeting shRNAs (#1-10) were treated with 1 μg/mL doxycycline for 6 days and PHGDH expression determined by western blot. β-actin is used as a loading control.

The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.

The TIGAR protein has antioxidant activity that supports intestinal tissue repair and adenoma development. Using a pancreatic ductal adenocarcinoma (PDAC) model, we show that reactive oxygen species (ROS) regulation by TIGAR supports premalignant tumor initiation while restricting metastasis. Increased ROS in PDAC cells drives a phenotypic switch that increases migration, invasion, and metastatic capacity. This switch is dependent on increased activation of MAPK signaling and can be reverted by antioxidant treatment. In mouse and human, TIGAR expression is modulated during PDAC development, with higher TIGAR levels in premalignant lesions and lower TIGAR levels in metastasizing tumors. Our study indicates that temporal, dynamic control of ROS underpins full malignant progression and helps to rationalize conflicting reports of pro- and anti-tumor effects of antioxidant treatment.