1. Metastasis-intrinsic Metabolic Adaptations

Work in my lab has identified novel glucose metabolizing reactions that synthesize rate-limiting substrates required for activation of phosphogluconate dehydrogenase (PGD, or 6PGD). PGD is a highly oncogenic biosynthetic enzyme that is selectively activated in widely metastatic pancreatic cancers. Many of these glucose-fueled reactions are ancient remnants of the ascorbic acid (Vitamin C) biosynthetic pathway, which was discarded during the evolution of some primates including humans. Synthesis of rate-limiting PGD substrates through these remnant reactions is a selectable trait since PGD catalysis directly converts those metabolites into potent biosynthetic products (ribulose, NADPH) that fuel rapid metastatic outgrowth. This suggests that metastatic cancers may adopt their own unique metabolic reactions to promote or even accelerate metastatic outgrowth as a terminal event during cancer progression.

2. Pro-metastatic Positive Feedback Loops

TXNIP is a protein that maintains intracellular glucose homeostasis by removing glucose transporters off the cell surface as glucose consumption rates rise to excessive levels (negative feedback). We have found that high PGD catalysis suppresses TXNIP transcription by preventing nuclear translocation of MLX-related transcription factors. PGD-driven suppression of TXNIP therefore allows glucose consumption rates to rise to abnormally high levels even within glucose-replete microenvironments, as found along certain metastatic routes. The excess glucose is then metabolized into rate-limiting substrates that reciprocally fuel additional rounds of PGD catalysis (positive feedback). Constant replenishment of rate-limiting substrates through excessive glucose import thereby constitutively activates PGD even though PGD itself is not mutated, amplified, or over-expressed. These findings raise the possibility of pro-metastatic positive feedback loops (PGD-glucose) that eliminate negative feedback opposition (TXNIP-glucose) to produce overtly malignant adaptable traits that are not themselves genetically encoded.

3. Adaptive Metaboloepigenetics

Another selectable byproduct of PGD-driven positive feedback is glucose-fueled synthesis of downstream metabolites that globally reprogram chromatin. Suppression of TXNIP allows excessive glucose import, which can generate additional metabolite byproducts (for example, acetyl CoA) that stimulate catalytic activities of chromatin modifying enzymes in the nucleus. A major consequence is that these enzymes can now reprogram the metastatic epigenome into a globally hyperacetylated chromatin state that is permissive for activation of the metastatic transcriptome. The resulting metaboloepigenetic program is highly adaptable and therefore selectable within nutrient replete microenvironments, as found along the distant metastatic routes.